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Regulatory T (Treg) cells, an immunosuppressive subset of CD4+ T cells characterized by the expression of the master transcription factor forkhead box protein P3 (FOXP3), are a component of the immune system with essential roles in maintaining self-tolerance. In addition, Treg cells can suppress anticancer immunity, thereby hindering protective immunosurveillance of neoplasia and hampering effective antitumour immune responses in tumour-bearing hosts, thus promoting tumour development and progression. Identification of the factors that are specifically expressed in Treg cells and/or that influence Treg cell homeostasis and function is important to understanding cancer pathogenesis and to identifying therapeutic targets. Immune-checkpoint inhibitors (ICIs) have provided a paradigm shift in the treatment of cancer. Most immune-checkpoint molecules are expressed in Treg cells, but the effects of ICIs on Treg cells, and thus the contributions of these cells to treatment responses, remain unclear. Notably, evidence indicates that ICIs targeting programmed cell death 1 (PD-1) might enhance the immunosuppressive function of Treg cells, whereas cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors might deplete these cells. Thus, although manipulation of Treg cells is a promising anticancer therapeutic strategy, approaches to controlling these cells require further research. Herein, we discuss novel insights into the roles of Treg cells in cancer, which can hopefully be used to develop Treg cell-targeted therapies and facilitate immune precision medicine.Regulatory T (Treg) cells are implicated in cancer immune evasion and escape and thus contribute to tumour development and progression. In this Review, the authors provide an overview of the phenotypes and roles of Treg cells in the context of cancer and outline potential strategies to target this cell type in anticancer immunotherapy.

Aging leads to numerous changes that affect many components of the immune system, called “immunosenescence”. Indeed, elderly individuals exhibit dysregulated immune responses against pathogens, poor responses to vaccination, and increased susceptibility to many diseases including cancer, autoimmune disorders, and other chronic inflammatory diseases. Despite progressed understanding of immunosenescence, its detailed mechanisms are still not fully understood. With advances in medicine, the population of older cancer patients is expected to rapidly increase in the coming years. Cancer immunotherapies, including immune checkpoint inhibitors (ICIs), have been shown to be effective for multiple cancer types, whereas to date, few specific data for elderly individuals have been published. Some systemic reviews have demonstrated that ICIs exhibit similar efficacy in older cancer patients, but they seem to be less effective in very old patients. In addition, toxicities might be more frequently observed in such patients. Here, we provide a summary to better understand immunosenescence and an overview of its relationship with cancer and antitumor immunity, including the efficacy and toxicity of ICIs.

Immune checkpoint inhibitors (ICIs) are effective for various types of cancer, and their application has led to paradigm shifts in cancer treatment. While many patients can obtain clinical benefits from ICI treatment, a large number of patients are primarily resistant to such treatment or acquire resistance after an initial response. Thus, elucidating the resistance mechanisms is warranted to improve the clinical outcomes of ICI treatment. ICIs exert their antitumor effects by activating T cells in the tumor microenvironment. There are various resistance mechanisms, such as insufficient antigen recognition by T cells, impaired T‐cell migration and/or infiltration, and reduced T‐cell cytotoxicity, most of which are related to the T‐cell activation process. Thus, we classify them into three main mechanisms: resistance mechanisms related to antigen recognition, T‐cell migration and/or infiltration, and effector functions of T cells. In this review, we summarize these mechanisms of resistance to ICIs related to the T‐cell activation process and progress in the development of novel therapies that can overcome resistance. While many patients can obtain clinical benefits from immune checkpoint inhibitor treatment, a large number of patients are primarily resistant to such treatment or acquire resistance after an initial response. There are various resistance mechanisms, and we classify them into three main mechanisms related to the T‐cell activation process: resistance mechanisms related to antigen recognition, T‐cell migration and/or infiltration, and effector functions of T cells.

Mitochondria are essential organelles that regulate various biological processes including metabolism. Beyond their intracellular functions, intercellular mitochondrial transfer has emerged as a novel mechanism of intercellular communication. Notably, an increasing number of studies have reported its occurrence in the tumor microenvironment (TME), where it contributes to tumor progression. While previous studies largely characterized cancer cells as recipients of mitochondria, Cangkrama et al. demonstrated that cancer cells donate their mitochondria to fibroblasts via tunneling nanotubes. The mitochondrial transfer to fibroblasts reprogrammed them into cancer‐associated fibroblasts exhibiting combined myofibroblastic and inflammatory characteristics, with enhanced oxidative metabolism and pro‐tumorigenic activity. Our group has identified mitochondrial ‘hijack’ from cancer cells to tumor‐infiltrating lymphocytes, leading to an impaired antitumor immunity. These insights underscore the need to recognize cancer cells as mitochondrial donors in the TME capable of reshaping the TME to their own advantage, resembling a dynastic expansion strategy that exerts influence by strategically placing lineages. Cangkrama et al. demonstrated that cancer cells donate their mitochondria to fibroblasts through mitochondrial transfer, reprogramming them into ‘MitoCAF’. Likewise, our group has identified mitochondrial transfer from cancer cells to tumor infiltrating lymphocytes, resulting in mitochondrial ‘hijack’ and impaired antitumor immunity. These findings highlight the need to consider cancer cells as mitochondrial donors within the tumor microenvironment.

Immune checkpoint blockade has provided a paradigm shift in cancer therapy, but the success of this approach is very variable; therefore, biomarkers predictive of clinical efficacy are urgently required. Here, we show that the frequency of PD-1 + CD8 + T cells relative to that of PD-1 + regulatory T (T reg ) cells in the tumor microenvironment can predict the clinical efficacy of programmed cell death protein 1 (PD-1) blockade therapies and is superior to other predictors, including PD ligand 1 (PD-L1) expression or tumor mutational burden. PD-1 expression by CD8 + T cells and T reg cells negatively impacts effector and immunosuppressive functions, respectively. PD-1 blockade induces both recovery of dysfunctional PD-1 + CD8 + T cells and enhanced PD-1 + T reg cell–mediated immunosuppression. A profound reactivation of effector PD-1 + CD8 + T cells rather than PD-1 + T reg cells by PD-1 blockade is necessary for tumor regression. These findings provide a promising predictive biomarker for PD-1 blockade therapies. Checkpoint blockade is effective in only a subset of patients; therefore, biomarkers that can predict efficacy would be clinically highly valuable. Nishkawa and colleagues develop a biomarker based on PD-1 positivity of effector and regulatory T cells in the tumor microenvironment that accurately predicts the effectiveness of checkpoint blockade in patients.

Combination therapy with anti‐cytotoxic T lymphocyte‐associated protein 4 (CTLA‐4) and anti‐programmed death‐1 (PD‐1) monoclonal antibodies (mAbs) has dramatically improved the prognosis of patients with multiple types of cancer, including renal cell carcinoma (RCC). However, more than half of RCC patients fail to respond to this therapy. Regulatory T cells (Treg cells) are a subset of highly immunosuppressive CD4+ T cells that promote the immune escape of tumors by suppressing effector T cells in the tumor microenvironment (TME) through various mechanisms. CTLA‐4 is constitutively expressed in Treg cells and is regarded as a key molecule for Treg‐cell‐mediated immunosuppressive functions, suppressing antigen‐presenting cells by binding to CD80/CD86. Reducing Treg cells in the TME with an anti‐CTLA‐4 mAb with antibody‐dependent cellular cytotoxicity (ADCC) activity is considered an essential mechanism to achieve tumor regression. In contrast, we demonstrated that CTLA‐4 blockade without ADCC activity enhanced CD28 costimulatory signaling pathways in Treg cells and promoted Treg‐cell proliferation in mouse models. CTLA‐4 blockade also augmented CTLA‐4‐independent immunosuppressive functions, including cytokine production, leading to insufficient antitumor effects. Similar results were also observed in human peripheral blood lymphocytes and tumor‐infiltrating lymphocytes from patients with RCC. Our findings highlight the importance of Treg‐cell depletion to achieve tumor regression in response to CTLA‐4 blockade therapies. CTLA‐4 blockade without ADCC activity augments the proliferation and CTLA‐4‐independent immunosuppressive functions of Treg cells by enhancing CD28 costimulatory signaling pathways in Treg cells, leading to insufficient tumor regression. This figure was created with BioRender.com.

The efficacy of programmed cell death–1 (PD‐1) blockade in patients with non–small cell lung cancer (NSCLC) positive for epidermal growth factor receptor (EGFR) gene mutations has been found to be limited, but the underlying mechanisms for this poor response have remained obscure. Given that the recognition by T cells of tumor antigens presented by major histocompatibility complex class I (MHC‐I) molecules is essential for an antitumor immune response, we examined the effects of EGFR tyrosine kinase inhibitors (TKIs) on MHC‐I expression in NSCLC cell lines. Appropriate EGFR‐TKIs increased MHC‐I expression at the mRNA and cell surface protein levels in NSCLC cells positive for EGFR mutations including those with the T790M secondary mutation. Trametinib, an inhibitor of the extracellular signal–regulated kinase (ERK) kinase MEK, also increased MHC‐I expression, whereas the phosphatidylinositol 3‐kinase (PI3K) inhibitor buparlisib did not, suggesting that the MEK‐ERK pathway mediates the down‐regulation of MHC‐I expression in response to EGFR activation. Immunohistochemical analysis of EGFR‐mutated NSCLC specimens obtained before and after EGFR‐TKI treatment also revealed down‐regulation of phosphorylated forms of EGFR and ERK in association with up‐regulation of MHC‐I, an increased number of infiltrating CD8+ T cells, and increased PD‐1 ligand 1 expression after such treatment. Our results thus suggest that mutational activation of EGFR inhibits MHC‐I expression through the MEK‐ERK pathway in NSCLC and thereby contributes to the poor response of such tumors to immunotherapy. Further studies are warranted to evaluate the relation between EGFR‐MEK‐ERK signaling in and the immune response to EGFR‐mutated NSCLC.  Mutational activation of EGFR inhibits MHC‐I expression through the MEK‐ERK pathway in NSCLC and thereby may contribute to the poor response of such tumors to immunotherapy.

By taking advantage of forward genetic analysis in mice, we have demonstrated that Pak1 plays a crucial role during DMBA/TPA skin carcinogenesis. Although Pak1 has been considered to promote cancer development, its overall function remains poorly understood. To clarify the functional significance of Pak1 in detail, we sought to evaluate the possible effect of an allosteric inhibitor against PAK1 (NVS‐PAK1‐1) on a syngeneic mouse model. To this end, we established two cell lines, 9AS1 and 19AS1, derived from DMBA/TPA‐induced squamous cell carcinoma (SCC) that engrafted in FVB mice. Based on our present results, NVS‐PAK1‐1 treatment significantly inhibited the growth of tumors derived from 9AS1 and 19AS1 cells in vitro and in vivo. RNA‐sequencing analysis on the engrafted tumors indicates that NVS‐PAK1‐1 markedly potentiates the epidermal cell differentiation and enhances the immune response in the engrafted tumors. Consistent with these observations, we found an expansion of Pan‐keratin‐positive regions and potentially elevated infiltration of CD8‐positive immune cells in NVS‐PAK1‐1‐treated tumors as examined by immunohistochemical analyses. Together, our present findings strongly suggest that PAK1 is tightly linked to the development of SCC, and that its inhibition is a promising therapeutic strategy against SCC. PAK1 inhibitor treatment significantly inhibited the growth of tumors derived from 9AS1 and 19AS1 cells in vitro and in vivo.

Background Several studies have established a correlation between the VEGF–VEGFR2 axis and an immunosuppressive microenvironment; this immunosuppression can be overcome by anti-angiogenic reagents, such as ramucirumab (RAM). However, little is known about the immunological impact of anti-angiogenic reagents within the tumor microenvironment in human clinical samples. This study aimed at investigating the effects of RAM on the tumor microenvironmental immune status in human cancers. Methods We prospectively enrolled 20 patients with advanced gastric cancer (GC) who received RAM-containing chemotherapy. We obtained paired samples from peripheral blood mononuclear cells (PBMCs) and tumor-infiltrating lymphocytes (TILs) in primary tumors both pre- and post-RAM therapy to assess immune profiles by immunohistochemistry and flow cytometry. Results Within the tumor microenvironment, both PD-L1 expression and CD8 + T-cell infiltration increased after RAM-containing therapies. In addition, CD45RA − FOXP3 high CD4 + cells (effector regulatory T cells [eTreg cells]) and PD-1 expression by CD8 + T cells were significantly reduced in TILs compared with PBMCs after RAM-containing therapies. Patients with partial response and longer progression-free survival had significantly higher pre-treatment eTreg frequencies in TILs than those with progressive disease. In in vitro analysis, VEGFR2 was highly expressed by eTreg cells. Further, VEGFA promoted VEGFR2 + eTreg cell proliferation, and this effect could be inhibited by RAM. Conclusions This study suggests that the frequency of eTreg cells in TILs could be a biomarker for stratifying clinical responses to RAM-containing therapies. Further, we propose that RAM may be employed as an immuno-modulator in combination with immune checkpoint blockade.

BACKGROUNDPrecise stratification of patients with non-small cell lung cancer (NSCLC) is needed for appropriate application of PD-1/PD-L1 blockade therapy.METHODSWe measured soluble forms of the immune-checkpoint molecules PD-L1, PD-1, and CTLA-4 in plasma of patients with advanced NSCLC before PD-1/PD-L1 blockade. A prospective biomarker-finding trial (cohort A) included 50 previously treated patients who received nivolumab. A retrospective observational study was performed for patients treated with any PD-1/PD-L1 blockade therapy (cohorts B and C), cytotoxic chemotherapy (cohort D), or targeted therapy (cohort E). Plasma samples from all patients were assayed for soluble immune-checkpoint molecules with a highly sensitive chemiluminescence-based assay.RESULTSNonresponsiveness to PD-1/PD-L1 blockade therapy was associated with higher concentrations of these soluble immune factors among patients with immune-reactive (hot) tumors. Such an association was not apparent for patients treated with cytotoxic chemotherapy or targeted therapy. Integrative analysis of tumor size, PD-L1 expression in tumor tissue (tPD-L1), and gene expression in tumor tissue and peripheral CD8+ T cells revealed that high concentrations of the 3 soluble immune factors were associated with hyper or terminal exhaustion of antitumor immunity. The combination of soluble PD-L1 (sPD-L1) and sCTLA-4 efficiently discriminated responsiveness to PD-1/PD-L1 blockade among patients with immune-reactive tumors.CONCLUSIONCombinations of soluble immune factors might be able to identify patients unlikely to respond to PD-1/PD-L1 blockade as a result of terminal exhaustion of antitumor immunity. Our data suggest that such a combination better predicts, along with tPD-L1, for the response of patients with NSCLC.TRIAL REGISTRATIONUMIN000019674.FUNDINGThis study was funded by Ono Pharmaceutical Co. Ltd. and Sysmex Corporation.