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Official websites use. Share sensitive information only on official, secure websites. Guorong Yan , Tongji University, China. This article was submitted to Cancer Genetics and Oncogenomics, a section of the journal Frontiers in Genetics. The use, distribution or reproduction in other forums is permitted, provided the original author s and the copyright owner s are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. In the tumor microenvironment, tumor-infiltrating immune cells TIICs are a key component. Different types of TIICs play distinct roles. In the meantime, a growing body of evidence illustrates that the balance between pro- and anti-tumor responses of TIICs is associated with the prognosis in the tumor microenvironment. Therefore, in order to boost anti-tumor response and improve the clinical outcome of tumor patients, a variety of anti-tumor strategies for targeting TIICs based on their respective functions have been developed and obtained good treatment benefits, including mainly immune checkpoint blockade ICB , adoptive cell therapies ACT , chimeric antigen receptor CAR T cells, and various monoclonal antibodies. In recent years, the tumor-specific features of immune cells are further investigated by various methods, such as using single-cell RNA sequencing scRNA-seq , and the results indicate that these cells have diverse phenotypes in different types of tumors and emerge inconsistent therapeutic responses. Hence, we concluded the recent advances in tumor-infiltrating immune cells, including functions, prognostic values, and various immunotherapy strategies for each immune cell in different tumors. Keywords: tertiary lymphoid structures, antigen presentations, immunotherapy, tumor-infiltrating immune cells, tumor microenvironment. Immunotherapies have become increasingly important for tumor patients, particularly those with advanced tumors Tarantino et al. It is well known that using immune checkpoint blockades ICBs has yielded a beneficial effect in patients with advanced melanoma and lung cancer Mehdizadeh et al. However, immunotherapy resistance occurs in some tumors, and a possible explanation for this condition is the complication of the tumor microenvironment TME Whiteside, TME, which is created by various cells and soluble molecules including immune cells and cytokines, exerts significant effects on tumor development and progression Duhan and Smyth, In TME, the crosstalk of immune cells and tumor cells significantly controls tumor growth, namely, cancer immunoediting Burnet, Cancer immunoediting involves three phases: elimination, equilibrium, and escape Dunn et al. In the elimination phase, various effector cells and molecules destroy tumor cells and dampen tumor progression. However, if immune cells can not eliminate tumor cells, cancer immunoediting might proceed into the equilibrium or escape phase. In the equilibrium phase, tumor cells could not be detectable and are deemed to be in a dormant status in the clinical. The cancer immunity cycle also consists of three phases: priming, migration, and effector. In the priming phase, the process of antigen-presenting is hampered by inhibitory signaling pathways, which impairs the activation of effector cells. In the migration phase, tumor cells release inhibitory molecules to restrain immune cell infiltration. In the effector phase, these mechanisms are even more complex. Immune cells infiltrating into the tumor sites perform diverse functions, thus, they influence tumor progression in various ways. The function of these immune cells will be discussed below Wada et al. Importantly, immune checkpoints ICs are essential for tumor progression in every phase. Over the past decades, attention given to ICs has increasingly grown. The ICs can be produced by various cells, including immune cells and tumor cells infiltrating the TME. They could cause the dysfunction of effector cells and inhibit the apoptosis of tumor cells Mehdizadeh et al. Apart from the immune cell components, cancer-associated fibroblasts CAFs and tumor endothelial cells ECs are associated with an aberrant vascular system that can transport nutrition to tumor cells and disturb the therapeutic delivery of T cells into the tumor sites Nagarsheth et al. It is well known that high demands for nutrients in tumor cells lead to the formation of abnormal vascular networks which promote tumor growth. Due to the intense competition for nutrients between tumor cells and immune cells, the nutrients and oxygen are insufficient in TME, causing a hypoxic and acidic status. Other substances metabolized by tumor cells, including hyper glycolysis, lactate, and lipid, can impede the antigen-presenting process of DCs, recruit regulatory T cells Tregs , and help tumor cells eventually escape from immune surveillance Davis et al. Additionally, soluble factors also deliver signals to control tumor development. Hereby, since the complex TME controls the benefits of immunotherapy, a comprehensive understanding of the complex components of tumor-infiltrating immune cells is required for tumor immunotherapy. In this review, we discussed the role of tumor-infiltrating immune cells in the process of tumor elimination in TME, as well as current immunotherapeutic strategies. In addition, we described the function and predictive value of tertiary lymphoid structures in TME. Tumor antigens could be recognized by DCs, which present antigens to T cells and activate T cells. This process is a pivotal step in the priming phase Eryn and Ott, Tumor antigens include mutant and viral antigens. Genomic aberrations of tumor cells result in mutant antigens, which affects antigens recognition and presentation Lu et al. Therefore, a comprehensive understanding of the antigen-presenting cells APCs is extremely critical. DC subsets are specialized in antigen recognition and presentation and induce a tumor-specific immune response in patients. XCL1 is also expressed by tumor cells, which boosts this process by activating T cells Matsuo et al. The function of pDCs is complicated for controlling tumor progression. Some studies have shown that higher pDC frequencies are correlated with worse outcomes Kvedaraite and Ginhoux, At this juncture, it is well documented that moDCs are the inflammation subsets and produce various inflammatory cytokines to induce tumor growth O'Keeffe et al. On the contrary, moDCs loading tumor antigens inhibit tumor progression by cross-presenting antigens, and this property has been considered as a therapeutic agent Ma et al. This tolerogenic property of DCs might help tumor cells escape from immune surveillance, limit effector T cells functions, boost the production and expansion of Tregs, and even induce DC apoptosis Mahnke et al. Furthermore, antigen presentation can also be influenced by tumor cells. During tumor development, tumor antigens can be lost or mutated, leading to the formation of neoantigens. Even with the assistance of HSP90, neoantigens are hidden by the tumor and result in the dysfunction of DCs Jaeger et al. Expression of the HLA-I complex is reduced by genetic alterations and the modulation of transcription, failing to recognize antigens Jhunjhunwala et al. However, while the deficiency is tumor-specific, how does an immune response recognize antigens? This issue requires an in-depth research Jhunjhunwala et al. DC-based immunotherapies : Given the properties of DCs and tumor antigens, using the cDC1-based vaccine in mice tumor can enhance infiltration of T cells and halt tumor progression Wculek et al. The cDC2-based vaccine may also potently inhibit tumor growth and prolong the survival Saito et al. In recent years, pDCs-based treatment has been developed and has acquired benefits. MoDCs-based vaccines have been generated, which loads tumor neo antigens for presentation to T cells. Researchers have also shown autologous DC-based vaccines in which tumor antigens are loaded could also be considered as a potential therapeutic strategy through delivering the antigen presenting cells Yewdall et al. Furthermore, nanomaterials with autophagy regulation have been developed, which is important for DC function and facilitates its anti-tumor activity Guan et al. Engineered exosomes to activate DCs have also been proposed and are considered as a promising method to develop Huang et al. Despite the fact that DC vaccines have acquired good efficacy in mouse models and clinical trials, they still face huge challenges as a treatment strategy, as DC vaccines could not be appropriate for a wide range of cancers. Intratumoral B cells switch isotypes and produce IgG or IgA antibodies, which is contradictory in influencing tumor growth Lauss et al. Therefore, the role of B cells is a double-edged sword Fridman et al. Some studies have proved that the fusion of antigen peptides loading on B cells can further enhance anti-tumor immune efficacy. Thus, researchers exploited this trait to edit a specific BCR toward tumor antigens in vitro. The editing BCR strategies are attractive, but they have are yet to be applied to treat tumors Page et al. Antibodies, targeting B cells, are mainly used to treat hematological malignancy, such as anti-CD19 and anti-CD20, which results in a conducive prognosis NCT , and currently, relevant trials are on the way. Activated T cells primarily eliminate tumor cells in TME. Hence, activated T cells need to migrate from blood vessels to the microenvironment with the influence of various molecules and constructions. Vascular endothelial growth factor expressed by tumor cells can promote tumor angiogenesis and inhibit the migration of activated T cells Nagarsheth et al. Recently, ectopic lymphoid aggregation has been discovered in the tumor sites, which resembles secondary lymphoid organs SLOs , termed tertiary lymphoid structures TLSs Dieu-Nosjean et al. Consequently, promoting immune cell migration into the TME could be a usable strategy to enhance anti-tumor immunity. Several studies have demonstrated that the combination of anti-PD-L1 and antiangiogenic therapy can facilitate intratumoral HEV formation and augment the efficacy of immunotherapies Allen et al. Intriguingly, this study has shown the depletion of Treg cells could drive HEV formation Colbeck et al. Therapeutic induction of HEVs with ACT immunotherapy promotes lymphocyte trafficking and enhances anti-tumor response, which is a promising strategy Lucas and Girard, Activated T cells recognize tumor cancer antigens on tumor cells by T-cell receptor TCR and release effector molecules to eliminate tumor cells. In TME, immune cells and tumor cells secrete and express various molecules to regulate tumor progression and metastasis. Herein, we discussed how immune cells affected tumor progression. They play significant roles in tumor immunotherapy by releasing a variety of molecules to hamper tumor growth. TSCM cells mostly localize in the lymph nodes and have the capacity for self-renewal. TEM cells produce integrins and chemokine receptors and traffic them into various tissues Masopust et al. In a mouse model, the finding suggested that TRM cell deficiency resulted in uncontrolled tumor growth with no change in the number of CD8 effector cells. Consequently, TRM cells are focused on gradually. They could also combine with E-cadherin on the surface of tumor cells to retain TRM in the tissue Zhang and Bevan, ; Ganesan et al. The expression of CD is highly heterogeneous. For instance, CD is essential in the skin, lung, and intestine Gebhardt et al. Moreover, CD49a also enhances the frequency of antigen encounters Bromley et al. These findings have a significant impact on immunotherapy for various tumors. Of note, although TRM cells play a crucial role in autoimmune diseases and viral infections, they are still in infancy in human tumors. According to the known functions of TRM cells, researchers have proposed some approaches to fortify the function of TRM cells and enhance anti-tumor response. Furthermore, in the preclinical melanoma model, using the combination of CD39 inhibitor and ICB made tumor growth retardation Sade-Feldman et al. Second, vaccines have been designed to treat tumors. Vaccines were also applied to generate TRM cells in mouse models of various infections Zens et al. Of note, few clinical trials have been performed to dissect TRM cell functions in different tumors Craig et al. For instance, what are the mechanisms by which TRM cells enhance anti-tumor immunity? Are the phenotypes consistent between normal tissues and tumor cells? Which phenotypes could define TRM? Therefore, these problems will trigger intense research. For example, after pathogens have been cleared, IL inhibits innate immunity and function of Th1 cells, which could maintain host immune homeostasis Couper et al. Th17 cells principally facilitate the death of extracellular bacteria and fungi Luckheeram et al. Because of the complicated function of Tfh cells and Treg cells in anti-tumor immunity, thus, we mainly discussed the roles of Tfh cells and Treg cells. Of note, CD28 is required for the differentiation of Tfh cells. If CD28 was deficient in T cells or reduced by its inhibitor, the differentiation of Tfh cells was blocked. Tfh cells also express ICOS. In addition, other cytokines have different roles to affect Tfh functions. Although Tfh cells have been explored, it is deficient for the mechanism of Tfh differentiation and the function of GCs in various tumors. Recently, studies have found that the presence of Tfh cells is important for upregulating CD8-dependent anti-tumor immunity and improving the benefit of anti-PD-L1 therapy in tumors Chen et al. Immune checkpoint inhibitors also facilitated Tfh cells to activate B cells and further improved the anti-tumor response in specific breast models Hollern et al. In a study, targeting Bcl6 — Blimp1 axis has been proposed to facilitate T cell differentiation, but the drug has not been generated Ciucci et al. These data provide a treatment strategy for Tfh cells, but it is required to further investigation for the role of Tfh cells in human tumors. Emerging evidence indicated that eTregs resulted in a poor prognosis, but non-Tregs infiltration in colorectal cancer CRC was associated with a favorable outcome Saito et al. Further analysis found that the prognostic value of intratumoral Tregs in various tumors is inconsistent Shan et al. In order to identify Tregs and dissect their functions, we must understand the phenotypes and cytokines expressed by Tregs. FOXP3 is a credible marker of Treg cells, and is essential for maintaining the function of Treg cells. Furthermore, antigen-specific Tregs could disturb the combination of the effector T cells and cognate antigen by interacting with APC Qu et al. Based on these immunosuppressive mechanisms of Tregs, researchers have proposed numerous noteworthy therapeutic strategies. First, the depletion of Tregs via anti-CD25 mAb daclizumab and toxin conjugated anti-IL-2 denileukin diftitox induced tumor regression and prolonged disease-free survival DFS in tumors Solomon et al. Despite the fact that anti-CD25 mAb could deplete Tregs in melanoma, it did not elicit an anti-tumor immune response Luke et al. Epigenetic modifiers have been designed to target genes that regulates FOXP3 expression on Tregs, leading to the depletion of Tregs. Third, CCR4 blockade may reduce the accumulation of Tregs in the tumor sites and improve therapeutic benefits in different types of cancers. It has been tested for the clinical response in phase 1 clinical trials in various solid tumors Shan et al. The combination therapy of galunisertib and ICIs further reduced Treg numbers in a mouse melanoma model, and this approach is being investigated in human tumor Ravi et al. Using the anti-GARP antibody, Sa, could lead to the depletion of Tregs and activate effector T cells in preclinical models, and this drug is being investigated in a clinical trial Shan et al. In brief, targeting T subsets is important for cancer immunotherapy. Despite enormous progress in the field, a further analysis needs to be conducted. Tertiary lymphoid structures which have been already mentioned are defined by an inner B-cell zone and an outer T-cell zone. B cells are indispensable for TLSs. These findings indicate B cell activation maybe undergo class-switch recombination CSR. Isotype class switching depends on different cytokines released by Tfh cells. IgG and IgA antibodies secreted by plasma cells could recognize tumor antigens and control tumor cell growth. It is reported that high-level IgG antibody in vitro was correlated with a worse prognosis in breast cancer patients, but IgA antibody in vitro that reacts to tumor antigens is associated with TLS presence in TME Garaud et al. In another study, a high-level IgG antibody is associated with a better immune response. Moreover, supernatants SNs , including IgG and IgA antibodies, were used to evaluate the immune responses to 33 tumor antigens, and the results were different Germain et al. Thus, the role of antibodies produced by GC B cells must be further explored. For the TLS formation, it is currently being explored, but researchers have demonstrated that the combination of 5-Aminoleuvulinic aminoleuvulinic acid-photodynamic therapy ALA-PDT and anti-PD-L1 mAb could promote the TLS formation and then enhance the clinical outcome in cutaneous squamous cell carcinoma Zeng et al. However, the research has shown that tumor-associated sensory neurons are negatively correlated with mature tertiary lymphoid-like structures and HEVs Vats et al. Growing evidence showed that TLSs were associated with clinical outcomes of cancer patients Schumacher and Thommen, Although TLSs were frequently correlated with a favorable prognosis in human tumors, but some studied have reported that TLSs were also linked to a negative correlation with clinical outcomes in hepatocellular carcinoma HCC and clear-cell renal carcinoma ccRCC Finkin et al. These inconsistencies might be explained by TLS heterogeneity, including TLS maturation state, location or detected phenotypes in tumors Jacquelot et al. With respect to TLS location, the prognostic values differ from tumor types. Compared to TLS situated in stromal tumor, the intratumoral and peritumoral mature TLSs were associated with a favorable prognosis Calderaro et al. Pancreatic cancer with intratumoral TLS signified a better prognostic value and exhibited a lower infiltration of immunosuppressive cells and higher infiltration of T and B cells compared to peritumoral TLS Hiraoka et al. TLSs could also predict the prognosis of patients with tumor metastases. In melanoma and breast cancer, no representative phenotypes of TLS was observed in brain metastases Cipponi et al. Besides, TLS density was related to primary tumor types in metastatic organs Remark et al. For example, TLS levels were found to be high in patients with lung metastases from colorectal and breast cancers. In preneoplastic hepatic lesions, immature TLSs did not effectively inhibit tumor cell growth Meylan et al. However, whether TLS is mature or not, its presence is associated with positive outcomes in oral squamous cell carcinoma Li et al. Remarkably, the most important factor should be the components of TLSs in various tumors. Tfh cells and B cells could express various chemokines to promote TLS formation. The presence of HEVs aids immune cells migration. These components have the potential to improve clinical outcomes. However, Tregs, the component of TLSs, play an immunosuppressive role and result in tumor growth Martinet et al. Moreover, it was reported that the plasma cells are crucial for the efficacy of ICB in the presence of TLS, but the molecular and cellular mechanisms for promoting plasma cells to response ICB are still unclear. However, the components still need to be explored in the future. Some studies also proposed that the density of TLSs varied at different stages of the tumor. Another study also reported that the number of TLS might be associated with the prognosis and could be considered as a target for treating patients with urachal carcinoma Zhang et al. Based on these conclusions, it is urgent to precisely understand the formation, components, and mechanism of TLS. Hence, a comprehensive analysis of TLS is an area of immense interest. Patients with cancer have different prognosis due to TLS heterogeneity. Compared to stromal TLS, intratumoral or both intratumoral and peritumoral mature TLSs were associated with a better prognosis in different tumors. Inducing or improving TLS function not only enhances anti-tumor responses, but also promotes the expansion of autoreactive T and B cells. First, the presence of intratumoral TLS has been regarded as a favorable marker of the responsiveness of ICB therapy in lung cancer, ccRCC, bladder cancer, urothelial carcinoma, melanoma and soft-tissue sarcoma Groeneveld et al. Second, therapeutic vaccination also induced TLS formation in specific tumors. In PDAC, a specific vaccine, an irradiated, allogeneic granulocyte—macrophage colony-stimulating factor—secreting pancreatic tumor vaccine GVAX , in combination with cyclophosphamide, was used to elicit TLS formation via suppressing the Treg pathway and activating the Th17 cell pathway. Lastly, the induction of HEV has already been elaborated Lutz et al. To sum up, the role of TLS has been stated above. Innate lymphoid cells ILCs are an important part of the immune system to defend against tumor cells on the front line. These cells, which lacks antigen-specific receptors, have different functions through secreting cytokines or activating specific signaling pathways. NK cells have the potential to mediate anti-tumor immunity via directly or indirectly killing tumor cells. CD56bright NK cells not only release a variety of cytokines, but also interact with various molecules secreted by other immune cells Fehniger et al. CD16 is the strongest activating receptor and a trigger to ADCC without the assistance of other receptors Bournazos et al. The natural cytotoxicity receptor family combined with tumor-associated ligands to remove malignant cells Kruse et al. Of note, soluble NKG2D ligands released by tumor cells have been reported to correlate with poor outcomes Lanier, ; Ferrari de Andrade et al. Likewise, soluble NKp30 ligand from tumor cells promoted tumor progression and metastasis Semeraro et al. On the surface of NK cells, inhibitory receptors also are expressed, which contains immunoreceptor tyrosine-based inhibitory motifs ITIMs Myers and Miller, As a side note, the KIRs have both activating and inhibitory functions Sivori et al. NK cell cytotoxicity was associated with clinical outcomes of cancer patients. These paradoxical observations are mainly based on the level expression of receptors or production of functional molecules. In the context of cancer, hILC1s have both a tumoricidal function and an immunosuppressive function. Several studies have shown that the presence of hILC1s has a paradoxical prognosis in various tumors Dadi et al. Intriguingly, one study found that hILC1s predominantly expressed activating receptors in the early stage of CRC, but they converted to expressing inhibitory receptors in the advanced stage Qi et al. Some studies have shown that a large number of hILC2s infiltrate and exert an anti-tumor effect in IL enriched the tumor sites Kim et al. These activities eradicated tumor cells in melanoma Jacquelot et al. However, IL also promotes tumor development and angiogenesis by various mechanisms Maggi et al. Accordingly, hILC2s have played both pro-tumor and anti-tumor roles. Additionally, IL is important to maintain and repair the epithelial barrier Goc et al. In human squamous cervical carcinoma and breast cancer, high-level IL played a pro-tumor role Punt et al. The phenotypes and functions of hILC subsets changed under different microenvironments. However, the conversion masochisms are still not a comprehensive explanation and are necessary to be explored. With the advent of cancer immunotherapy, targeting innate lymphoid cells has been reported. First, targeting inhibitory and activated NK cell receptors have been developed. Third, CAR-NK cell-based therapeutic regimens are considered as a promising therapeutic method, and increasing evidence has been shown in the preclinical models. Additionally, it is intriguing that cytokines also are considered to add to the frame of CAR-NK cells. High doses of IL-2 have been applied to the clinical practice to treat a small part of patients with advanced tumors Marabondo and Kaufman, , but IL-2 could increase the number of Tregs Ghiringhelli et al. Furthermore, researchers found utilizing IL did not result in Tregs expansion in patients with neuroblastoma Nguyen et al. Consequently, IL which increases the number and function of NK cells, is considered as a therapeutic strategy. It is surprising that ALT can attach to other molecular structures in order to generate a pleiotropic compound and obtain benefits Sivori et al. Treatment with the combination of human IL rhIL and monoclonal antibody, including alemtuzumab, obinutuzumab, avelumab, or mogamulizumab, has been reported to boost the cytotoxicity of NK cells and enhance the efficacy of these monoclonal antibodies in small population patients with advanced chronic lymphocytic leukemia Dubois et al. Another cytokine, IL, is of a similar anti-tumor function to IL The injection of membrane-bound interleukin 21 mbIL after haploidentical HSCT of patients with leukemia reduced the risk of relapse Ciurea et al. Additionally, the combination therapy of IL and IL was used in rhabdomyosarcoma to enhance anti-tumor response Wagner et al. Lastly, novel polyfunctional antibodies, termed natural killer cell engagers NKCEs , have been generated. NKCEs have been proposed to generate a more effective benefit against tumor cells Davis et al. Furthermore, new tri-specific killer cell engagers TriKE have been designed. They induced NK cells to secret cytokines and eliminate tumor cells Demaria et al. The various NKCE strategies are promising therapeutic tactics and are necessary to be further explored. At present, harnessing helper ILCs is relatively rare and mainly targets cytokines that influence the cytotoxicity of these cells. IL is a key molecule in this axis. Targeting the IL receptor on tumor cells has shown a good efficacy in glioma mouse model. It is well known that using anti-IL-4R antibodies had a significant impact on a variety of tumors Yang et al. The function and plasticity of helper ILCs are important for tumor therapy. Thus, increasing research into helper ILCs should be conducted in the future. Myeloid-derived suppressor cells have been reported as inhibitors of anti-tumor immunity by antigen-specific and non-specific patterns Serafini et al. Some researchers have shown that MDSCs are negatively associated with the prognosis of tumor patients Serafini et al. First, depletion of MDSCs has been carried out in mouse models. Another novel therapeutic strategy has been proposed. Second, it is a practical strategy that MDSCs are blocked to migrate to the tumor sites. CXCR2 antagonists have been reported to make MDSCs range from overt infiltration to subtle infiltration and T-cell infiltration increase in the tumor sites. Third, the downregulation of immunosuppressive functions of MDSCs is a promising approach. In preclinical models of glioma, targeting COX2 combined with acetylsalicylic acid downregulated the levels of PGE2 and inhibited glioma progression Fujita et al. Lastly, another credible strategy is to reduce the production of MDSC populations. All-trans-retinoic acid ATRA binding to the retinoid receptor could induce the immature myeloid cell IMC population to differentiate into macrophages and dendritic cells, neutralize high ROS production and increase glutathione synthase Liu et al. ATRA administration or combined with other immunotherapies increased the number of T cells, enhanced dendritic cell functions, and downregulated the ROS generation in MDSCs, resulting in improving anti-tumor immunity Li et al. The combination of ATRA and ipilimumab are more effective than using ipilimumab monotherapy alone in metastatic melanoma and cervical cancer patients Tobin et al. ATRA administration is an extremely promising therapeutic option for restraining the immunosuppressive functions of MDSCs, thus, its application needs to be further explored in other tumors. Other approaches to impact the differentiation and function of MDSCs, such as promoting the expression of interferon regulatory factor IRF -8, and inhibiting casein kinase 2 CK2 signaling, are promising strategies Valanparambil et al. In summary, targeting MDSCs have been developed and acquired good outcomes in preclinical models. Thus, further studies are indispensable in the different tumor types. Secondly, the plasticity of MDSCs has been mentioned previously. Thus, the factors which reshape the differentiation of MDSCs are essential for future treatment strategies. In addition, even if the depletion of MDSC and the inhibition of MDSC trafficking are favorable options, the complicated mechanisms to reduce the number of MDSCs have not been revealed, so complementary researches are cardinal to develop new options and improve the prognosis. Macrophages have been traditionally divided into two types: inflammatory M1-macrophages anti-tumoral phenotypes and immunosuppressive M2-macrophages pro-tumoral phenotypes Cassetta and Pollard, ; Christofides et al. Macrophages are recruited into the tumor sites and play different functions, termed tumor-associated macrophages. CSF1 is a key factor for the recruitment of macrophages and polarizes macrophages to express the M2 phenotype De et al. CCL2 also attracts macrophages into the tumor sites and mediates macrophage polarization Korbecki et al. TAMs have a dual function, pro-tumoral and anti-tumoral functions. TAMs promote tumor progression by following pathways. First, TAMs release various molecules to assist tumor cell proliferation and metastasis. Second, TAMs play an immunosuppressive role by expressing various small molecules. Conversely, TAMs could inhibit tumor progression by increasing their phagocytic capacity and enhancing the function of antigen presentation. Of note, the polarization of macrophages could be reshaped in the complex TME. For instance, activated mTOR signaling pathways facilitated the polarization of M2 macrophages Mazzone et al. Targeting TAMs mainly inhibits its pro-tumoral functions, and several studies have been conducted. The efficacy of CSF-1 and CCL2 inhibitors has been comprehensively reviewed, therefore, we will not be covered here reviewed in refs Rasmussen and Etzerodt, Second, inhibition of the immunosuppressive function of TAMs could boost anti-tumor immunity by polarizing M2 TAMs into anti-tumor phenotypes. Upon a TLR agonist, targeted delivery of a long peptide antigen to TAMs via using a nano-sized hydrogel nanogel activated TAMs to promote tumor apoptosis and activate anti-tumor immune responses, including antigen-presenting activity and altering tumor immune responses from resistance to responsiveness Muraoka et al. Third, restoring phagocytic capacity is crucial for TAMs. Anti-CD47 antibodies have also been reported to strengthen the anti-tumor activity of macrophages Brierley et al. At present, a novel method, targeting TAMs with nanomaterials, has been reported. The use of nanomaterials to inhibit tumor growth not only promotes anti-tumor immunity, but it also reduces the off-target effects and adverse events. The details of nanoimmunotherapies for TAMs have been concluded in this review Kumari and Choi, Therefore, targeting nanoimmunotherapies is a promising option. Thus, more research is needed in the future. In brief, although these therapeutic strategies have been successfully applied in mouse models and even in the clinical trials, targeting TAMs is still limited. At present, targeting all macrophage populations is less effective than targeting pro-tumor TAMs, so researchers want to further focus on targeting a specific macrophage population to reach maximal efficacy. Thus, further exploration needs to dissect the mechanisms of TAM polarization from top to bottom and develop novel treatment agents. Thus, extensive investigations about targeting these molecules needs to be performed. Finally, the combination therapy of based-TAM and other ways like radiotherapy are also worthy of research. With the advancement of immunotherapies, it is well revealed that tumor-infiltrating immune cells play increasingly important roles and interact with the efficacy of targeting these immune cells. Therefore, the dissection of these cell properties in TME is indispensable for improving the clinical response of immunotherapies. In this review, we have dissected the characteristics of mainly tumor-infiltrating immune cells, including their phenotypes, their recruitment, their activation, and immune-based therapies Figure 2. The interactions with these cells in TME are complicated due to the presence of anti-tumor and pro-tumor activities, which is associated with the clinical outcome of cancer patients. In addition, these cells also form a special structure which impacts the clinical outcome of tumor patients, but it remains in its infancy for TLS properties. Correspondingly, according to the characteristics of these immune cells, various immunotherapy approaches have been developed and are successful in preclinical tumor models and human tumors, including targeting cytokines and chemokines, targeting various phenotypes, and CAR-T. Recently, nanoimmunotherapies have been generated and acquired a better efficacy, which provides a novel approach to target tumor cells and is worthy of emulation. However, due to the conspicuously complex TME, the clinical response of some strategies is limited, even ineffective and resistant. Consequently, extensive complementary researches on tumor-infiltrating immune cells are necessary to overcome these shortcomings and further develop curative tactics for a conducive prognosis. Tumor-infiltrating immune cells are important. Different cells play different roles. Tumor cells also secrete various molecules to disturb immune cell function. These molecules can convert cell phenotype and change their function, like NK cells. The crosstalk of these immune cells are is important for their function. Inhibitory cells secrete various immunosuppressive molecules to impair the cytotoxicity of effector cells. Obtained funding: LR. Supervision: LR and HN. All authors contributed to the article and approved the submitted version. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors, and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. This section collects any data citations, data availability statements, or supplementary materials included in this article. As a library, NLM provides access to scientific literature. Front Genet. Find articles by Wang Yaping. Find articles by Wang Zhe. Find articles by Chu Zhuling. Find articles by Li Ruolei. Find articles by Fan Pengyu. Find articles by Guo Lili. Find articles by Ji Cheng. Find articles by Zhang Bo. Find articles by Liu Liuyin. Find articles by Hou Guangdong. Find articles by Wang Yaoling. Find articles by Hou Niuniu. Find articles by Ling Rui. Received Jul 7; Accepted Aug 29; Collection date Open in a new tab. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel. Tarantino et al. Mehdizadeh et al. Martinez and Moon, Tumor-specific TRMs have a role in limiting the invasion of the tumor into the other tissues. Munari et al. Nagarsheth et al. Lamplugh and Fan, Davis et al. Eryn and Ott. TRM cells infiltrating the tumors are linked to lower tumor stage. Lu et al. Kvedaraite and Ginhoux, Bogunovic et al. Roberts et al. Matsuo et al. Schoenberger et al. Chow et al. Stratikos et al. Garris et al. Mikucki et al.

Buy weed online in Serre Chevalier

Accueil Dossiers Specialised Centralities of Outdo This notion offers a complement to territorial models of tourism, as it identifies small clusters that do not fit into either the category of tourist resorts or that of dispersed tourism. The notion takes into account both the spatial characteristics of these places and the way in which they are practised. This paper is based on field research carried out in major hotspots of outdoor sport tourism, and is illustrated in particular with the case of the Haute-Durance basin. The different dimensions of specialised centralities are outlined: material qualities, symbolic values and community co-presence. Examples of particularly isolated specialised centralities are presented in order to emphasise their modest dimensions in terms of territorialisation and economic activity. However, the different ways in which specialised centralities are integrated in the tourist fabric and the territory are also evoked. The phenomenon is therefore closely studied by territorial economy Gumuchian and Pecqueur, , and the public and professional debate is largely focused on the ways of turning these sport activities into a source of income and employment for territories Derioz et al. However, contemporary changes affecting tourism are reshaping the territories, weakening some organisational logics and generating others Tuppen and Langenbach, Finally, in some other places, outdoor sport tourism is just one activity among others within diversified presential economies. The article proposes to situate specialised centralities within these various territorial forms, in order to grasp more clearly the specific contribution of outdoor sport tourism to the territorial and economic construction of tourist space. The article suggests that this contribution is often modest in terms of presential economy; however, analysing these specialised practices, in their material as well as ideal or symbolic dimensions, gives keys to understand the powerful values attributed to certain places and spaces by certain practices, and the concrete, local effects of this valorisation. The various practices or modes of practice create sites with very different geometries and dimensions Figure 1. The relationships between the sites and the spatialities of the tourists are very different in these two cases. Sport sites are therefore not destinations in themselves. On the other hand, specialised sport tourism is the result of a precise selection and hierarchy of different sites by outdoor sports: some, considered particularly beautiful or interesting, attract people who come to stay in the area specifically to practise their sport in these sites. In this perspective, the site is, roughly speaking, the terrain practised during the day, or between two motorised trips; it is the place in which one settles, or which one moves across, for a period of at least a few hours. Such a definition may cover vast areas, for example the Haute-Durance basin for kayaking Figure 1. The issue of territorial development has been a major focus of social science research on outdoor sports, particularly in geography. These sport communities are often characterised by cultural codes and practices that value marginality, or avoidance of commercial practices wild camping, self-sufficient practice rather than being guided, etc. It is this gap that this article seeks to fill. The analyses in this article are based on all these case studies; however, for the sake of synthesis, the discussion here is mainly illustrated by one of the areas studied, the Haute-Durance basin Figure 1. This diversity is reflected in the spatial and territorial forms of tourism, from winter sports resorts to remote hamlets and small urban centres. The network of outdoor sport sites is also dense and diverse, with small sites of local interest as well as world-class sites, and major centres for commercial, general public outdoor sport activity. The case of the Haute-Durance shows various types of outdoor sport tourism specialised centralities, and various forms of territorial integration of these centralities. However, most of the empirical work consisted of a campaign of interviews and participant observation conducted in and In the major hotspots indicated above, I targeted people who stayed there on a tourism trip expressly dedicated to the practice of sport, and I met them on the sport sites or in the accommodation close to these sites. I conducted 76 semi-structured interviews, about 15 per study site, sometimes with several people, for a total of people interviewed. The questions focused on the relationship to the practice sites and their valorisation, as well as on the patterns of mobility and action in this form of tourism. The interview thus allowed for a detailed understanding of the way in which the places and environments of outdoor sport tourism are practised. Drawing from a sum of individual experiences, this approach allows viewing sport tourism places through the practices that define them. Quotes from these interviews will give some insights into these practices. Figure 1 : The Haute-Durance, a multi-sports region that hosts several global centralities of outdoor sport tourism. Adapted from Geffroy, There are therefore primary conditions: a river and sufficient water for kayaking, a rock face for climbing, an elevation drop and areas suitable for take-off and landing for paragliding, for instance. But outdoor sport sites are also distinguished by many other more precise, sometimes subtle, material criteria, which lead to a hierarchy in terms of interest and aesthetics. Many of these criteria play a role both in terms of their suitability for the material aspects of the sport fluidity, safety, sport difficulty, originality of movements, sensations, etc. The suitability of a place is also assessed in terms of the potential for the specific sport activity, i. This status is linked to the frequentation by members of the community of practice and social media coverage, and to the attribution of positive values and to circulation of these values within the community Ponting and McDonald, Attraction is therefore not only practical, but also refers to the values that are attached to places. Their reputation is largely maintained by the community Woermann, , as well as by the specialised media; sports hotspots are rarely the subject of real tourism marketing strategies. Such social interactions are almost invariably cited as one of the major factors of attraction, complementary to, or even as important as, the sport qualities of the sites Geffroy, , p. The capacity of places to bring the community together is also linked, on a practical level, to their relative proximity to population centres and transport infrastructures, but also to other tourist infrastructures and centres. Some sites may be mythical, particularly beautiful or particularly abundant in sport potential, and yet constitute very limited centralities due to their remoteness, or their distance from the main countries or regions of the sport community—outdoor sport tourism still remains overwhelmingly an activity of the wealthy Western world. Valleys such as the Gyronde and the Guisane thus find in kayaking one of the relays, in spring and summer, of the winter sports activity, which was the source of the main tourist developments—such as the resorts of Serre-Chevalier and Puy-Saint-Vincent. Thus, hotspots of outdoor sports often only have a modest impact on the territory and its economic activities. Such places are located away from other tourist centres, and their tourist economy is essentially dependent on a specific sport site and a specific sport community. As the community consists mainly of self-sufficient sport participants, there is little to no demand for supervision, and thus the economy is mostly limited to a handful of accommodation and food establishments, i. Production: Geffroy. Indeed, this degree of development is generally only achieved by multi-sport tourist centres, the canonical example of which would be Chamonix, a major centre for mountaineering, skiing, but also climbing, paragliding or even trail running. Specialised centralities of outdoor sports can indeed constitute autonomous centres, but their development remains generally very limited. The largest part of the income of paragliding schools is generated by tandem flights Perrin-Malterre, , and the largest part of the activity of white-water instructors consists of rafting, canorafting or hydrospeed tours Marsac, —all activities accessible to a large public. Although we have noted above that there is a certain decoupling between the general public and specialised sport tourism sites, this is not always the case: some specialised sport tourism hotspots are also major spots for the general public, such as the Ubaye river Figure 1 for kayaking and rafting, or the paragliding take-offs of Talloires and Montmin above Lake Annecy; there, it is mainly to this second category of practice that the tourist economic activity is due, and not to the status of hauts lieux that they have within the passionate sport community. For example, the town of Guillestre is a small tourist centre which benefits from a variety of activities: holiday residence, hiking, heritage visits and a variety of mountain sports. Kayakers are present there in fairly large numbers, but their share in the clientele of the many accommodation and restaurant establishments is hard to assess. However, specialised centralities remain decisive in the spatial and temporal organisation of outdoor sport tourism practices, which remain polarised by the sport sites and leave little room for other activities in the tourist stay. In Guillestre, for instance, the presence of kayakers is due in particular to the proximity of the navigable sections of the Guil river. Asking the participants of outdoor sport tourism allows to estimate their propensity to engage in activities other than their sport during their stay Geffroy, , p. Even among those who say they engage in non-sport activities, these are generally clearly subject to the imperative of not interfering with the main sport. However, the insertion of hauts lieux in important tourist centres increases the propensity to engage in other tourist practices. As a spatial concentration of built facilities and of the sporting community, mainly around accommodation, specialised centrality is distinct from dispersed tourism Bourdeau, But some of them, mainly the hauts lieux , form sport tourism destinations and small centres of activity—these are the specialised centralities. They differ from tourist resorts , although they share a specialisation in one activity, in that they only attract a niche activity, and not a tourist practice which is widespread in the general population, such as beach holidays or winter sports. The specialised centrality is therefore generally smaller, both spatially and economically, than the resort. The specialised centrality may be isolated, forming in this case a clearly distinct tourist place; or inserted in a tourist resort or even in an urban centre. In this second case, the specialised centrality does not constitute a distinct territorial form, but remains a secondary centrality with specific spatialities, in relation to the site or sites of practice on which it depends. He argues that it allows to free the analysis from the structuralist model of urban central places, and to consider that places are central according to the way in which they are inhabited—through residence and daily work, or through temporary accommodation and leisure, etc. If considering tourist centralities allows us to de-centre the analysis from the organisation of the territory by urban centres, considering specialised tourist centralities allows us to de-centre from the organisation of the tourist territory by main centres urban centres, towns, resorts. In both cases, the reading of space is refined by differentiating practices, and by admitting that different practices construct different places; in this case, each sport practice defines its own perimeters and its own spatialities. Specialised tourist centralities also invite us to understand attractiveness at different scales and according to different audiences: outdoor sport tourism can indeed create centralities of global attraction for a specific community of practice, but of little importance within the urban network or the regional tourism space. This economic sphere depends essentially on the attractiveness of territories, both for residents and tourists. Taking into account specialised centralities makes it possible to grasp the precise qualities of places that attract particular, more or less temporary, more or less concentrated presences. Of course, places do not attract tourists without a certain amount of valorisation work by local actors, which may be called development or territorialisation Mao and Corneloup, ; Mao, Corneloup and Bourdeau, ; but thinking in terms of the presential economy makes it possible to grasp the challenge of valuing presences that are due to a territorial resource, rather than focusing on the means of developing an activity. In the perspective of the sustainability of the presential economy, specialised centralities have the benefit of being relatively autonomous in their valorisation by a community and a specific practice, and can rely on a certain loyalty linked to the consubstantial relationship between the community, the practice and the resource. On the other hand, specialised centralities have the disadvantage of a limited potential for the development of alternative tourist activities—unless, of course, they succeed in attracting other practices, and thus diversifying the tourist centrality. The specialised centrality evokes a model of tourism economy that is intermediate between the resort and dispersed tourism, relying on an archipelago of modest centralities and diverse activities, rather than on large-scale land development projects; and a model of tourism economy based on existing resources and a fine-tuned understanding of diverse leisure and travel practices. The article demonstrates the value, for the geography of tourism and for territorial economy, to regard specialised centralities as a type of tourist place, autonomous or inserted, but always presenting specific spatialities and a specific frequentation. The concept encourages to ground the analysis in the practices of tourists in and with places, in order to grasp precisely the sources of the attractiveness of places, and the spatialities that result from the specialised practices of places, in this case outdoor sport tourism. In this way, the major importance and the global centrality of certain hotspots for specific communities can be grasped, whereas the perspective of territorial and tourist development at first sight only sees small centres with very limited activity and little influence on the tourist economy, or niche activities in a diversified tourist offer. Rural areas in particular turn towards more modest and locally rooted forms of development, based on a diversity of place-based practices, as a privileged path towards the resilience of territories Broegaard, Outdoor sport tourism, as a practice deeply rooted in unique places, generating hauts lieux and specialised tourist centres, can contribute to this multi-faceted valuation of territories. Bourdeau P. Corneloup ed. Du Fournel. Broegaard R. Brookes A. Corneloup J. Debarbieux B. Hopes, fears and realities , coll. Derioz P. Approche sur le cas des Hautes-Alpes. Everts J. Fletcher R. Geffroy V. Gumuchian H. Higham J. Langenbach M. Mao P. Marsac A. Moularde J. Pecqueur B. Perrin-Malterre C. Ponting J. Rickly-Boyd J. Duncan, S. Cohen et M. Thulemark eds. Stock M. Bernard, C. Blondy et P. Duhamel eds. Thorpe H. Tuppen J. Weed M. Woermann N. Institute of Geography and Sustainability, University of Lausanne. Voir la notice dans le catalogue OpenEdition. Navigation — Plan du site. Keywords: specialised centrality , outdoor sport tourism , territory , presential economy. Sites and G rounds of O utdoor S ports. Territorial C onfigurations of O utdoor S port T ourism. Specialised C entralities and T ourism I solates. Isolated C entralities and their M odest E conomic I mpact. Tourism T erritories and I ntegration of S pecialised C entralities. Tourism, T erritories and c entralities: R efining the A pproach. Territorial C onfigurations of O utdoor S port T ourism 7 To understand the territorial materialisation of outdoor sport tourism, it is essential to distinguish between general public tourism and specialised tourism, between sport sites and sport tourism destinations. Methods 9 The article is based on empirical material collected during field research carried out in several major hotspots of outdoor sport tourism Geffroy, Figure 1 : The Haute-Durance, a multi-sports region that hosts several global centralities of outdoor sport tourism Agrandir Original png, 1,5M. Lieux communs , Paris, Belin. Moments de lieux , Paris, Belin. Haut de page. Dans tout OpenEdition. Accueil Catalogue des revues OpenEdition Search. Tout OpenEdition. OpenEdition Freemium. Figure 1: The Haute-Durance, a multi-sports region that hosts several global centralities of outdoor sport tourism.

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