Recently emerging cancer immunotherapies combine the applications of therapeutics to disrupt the immunosuppressive conditions in tumor-bearing hosts. In this study, we found that targeting the proinflammatory cytokine IL6 enhances tumor-specific Th1 responses and subsequent antitumor effects in tumor-bearing mice. IL6 blockade upregulated expression of the immune checkpoint molecule programmed death-ligand 1 (PD-L1) on melanoma cells. This PD-L1 induction was canceled in IFNγ-deficient mice or CD4 T cell-depleted mice, suggesting that CD4 T cell-derived IFNγ is important for PD-L1 induction in tumor-bearing hosts. In some patients with melanoma, however, treatment with the anti-PD-1 antibody nivolumab increased systemic levels of IL6, which was associated with poor clinical responses. This PD-L1 blockade-evoked induction of IL6 was reproducible in melanoma-bearing mice. We found that PD-1/PD-L1 blockade prompted PD-1 macrophages to produce IL6 in the tumor microenvironment. Depletion of macrophages in melanoma-bearing mice reduced the levels of IL6 during PD-L1 blockade, suggesting macrophages are responsible for the IL6-mediated defective CD4 Th1 response. Combined blockade of the mutually regulated immunosuppressive activities of IL6 and PD-1/PD-L1 signals enhanced expression of T cell-attracting chemokines and promoted infiltration of IFNγ-producing CD4 T cells in tumor tissues, exerting a synergistic antitumor effect, whereas PD-L1 blockade alone did not promote Th1 response. Collectively, these findings suggest that IL6 is a rational immunosuppressive target for overcoming the narrow therapeutic window of anti-PD-1/PD-L1 therapy. These findings advance our understanding of IL6-PD1/PD-L1 cross-talk in the tumor microenvironment and provide clues for targeted interventional therapy that may prove more effective against cancer. .

This report describes generation of dendritic cells (DCs) and macrophages from human induced pluripotent stem (iPS) cells. iPS cell-derived DC (iPS-DC) exhibited the morphology of typical DC and function of T-cell stimulation and antigen presentation. iPS-DC loaded with cytomegalovirus (CMV) peptide induced vigorous expansion of CMV-specific autologous CD8 + T cells. Macrophages (iPS-MP) with activity of zymosan phagocytosis and C5a-induced chemotaxis were also generated from iPS cells. Genetically modified iPS-MPs were generated by the introduction of expression vectors into undifferentiated iPS cells, isolation of transfectant iPS cell clone and subsequent differentiation. By this procedure, we generated iPS-MP expressing a membranebound form of single chain antibody (scFv) specific to amyloid b (Ab), the causal protein of Alzheimer's disease. The scFvtransfectant iPS-MP exhibited efficient Ab-specific phagocytosis activity. iPS-MP expressing CD20-specific scFv engulfed and killed BALL-1 B-cell leukemia cells. Anti-BALL-1 effect of iPS-MP in vivo was demonstrated in a xeno-transplantation model using severe combined immunodeficient mice. In addition, we established a xeno-free culture protocol to generate iPS-DC and iPS-MP. Collectively, we demonstrated the possibility of application of iPS-DC and macrophages to cell therapy.

Gut dysbiosis caused by antibiotics impairs response to immune checkpoint blockade (ICB). Gut microbiota is becoming an attractive therapeutic target for cancer. The Clostridium butyricum MIYAIRI 588 strain is a probiotic therapy used to improve symptoms related to antibiotic-induced dysbiosis in Japan. We hypothesized that probiotic Clostridium butyricum therapy (CBT) may affect the therapeutic efficacy of ICBs. We retrospectively evaluated 118 advanced non-small cell lung cancer patients treated with ICBs at Kumamoto University Hospital. Survival analysis comparing patients given CBT before and/or after ICB was conducted using univariate analyses and Cox proportional hazards regression models using propensity score. Propensity score analyses confirmed that probiotic CBT treatment significatnly prolonged PFS and and OS. Probiotic CBT significantly associated with longer PFS and OS even in patients who received antibiotic therapy. This study suggests that probiotic CBT may have a positive impact on therapeutic efficacy of ICB in cancer patients. Research.

TRAIL is known to play a pivotal role in the inhibition of autoimmune disease. We previously demonstrated that administration of dendritic cells engineered to express TRAIL and myelin-oligodendrocyte glycoprotein reduced the severity of experimental autoimmune encephalomyelitis and suggested that CD4+CD25+ regulatory T cells (Tregs) were involved in mediating this preventive effect. In the current study, we investigated the effect of TRAIL on Tregs, as well as conventional T cells, using TRAIL-deficient mice. Upon induction of experimental autoimmune encephalomyelitis, TRAIL-deficient mice showed more severe clinical symptoms, a greater frequency of IFN-γ–producing CD4+ T (Th1) cells, and a lower frequency of CD4+Foxp3+ Tregs than did wild-type mice. In vitro, conventional T cells stimulated by bone marrow-derived dendritic cells (BM-DCs) from TRAIL-deficient mice showed a greater magnitude of proliferation than did those stimulated by BM-DCs from wild-type mice. In contrast, TRAIL expressed on the stimulator BM-DCs enhanced the proliferative response of CD4+CD25+ Tregs in the culture. The functional TRAILR, mouse death receptor 5 (mDR5), was expressed in conventional T cells and Tregs upon stimulation. In contrast, the decoy receptor, mDc-TRAILR1, was slightly expressed only on CD4+CD25+ Tregs. Therefore, the distinct effects of TRAIL may be due to differences in the mDc-TRAILR1 expression or the signaling pathways downstream of mouse death receptor 5 between the two T cell subsets. Our data suggest that TRAIL suppresses autoimmunity by two mechanisms: the inhibition of Th1 cells and the promotion of Tregs.

Methods have been established to generate dendritic cells (DCs) from mouse and human embryonic stem (ES) cells. We designated them as ES-DCs and mouse models have demonstrated the induction of anti-cancer immunity and prevention of autoimmune disease by in vivo administration of genetically engineered ES-DCs. For the future clinical application of ES-DCs, the histoincompatibility between patients to be treated and available human ES cells and the ethical concerns associated with human ES cells may be serious obstacles. However, recently developed induced pluripotent stem (iPS) cell technology is expected to resolve these issues. This report describes the generation and characterization of DCs derived from mouse iPS cells. The iPS cell-derived DCs (iPS-DCs) possessed the characteristics of DCs including the capacity of T-cell-stimulation, antigen-processing and presentation and cytokine production. DNA microarray analyses revealed the upregulation of genes related to antigen-presenting functions during differentiation into iPS-DCs and similarity in gene expression profile in iPS-DCs and bone marrow cell-derived DCs. Genetically modified iPS-DCs expressing antigenic protein primed T-cells specific to the antigen in vivo and elicited efficient antigen-specific antitumor immunity. In addition, macrophages were generated from iPS cells (iPS-MP). iPS-MP were comparable with bone marrow cell-derived macrophages in the cell surface phenotype, functions, and gene expression profiles.

Introduction The emergence of SARS‐CoV‐2 has caused global public health and economic crisis. Human leukocyte antigen (HLA) is a critical component of the viral antigen presentation pathway and plays essential roles in conferring differential viral susceptibility and severity of diseases. However, the association between HLA gene polymorphisms and risk for COVID‐19 has not been fully elucidated. We hypothesized that HLA genotypes might impact on the differences in morbidity and mortality of COVID‐19 across countries. Methods We conducted in silico analyses and examined an association of HLA gene polymorphisms with prevalence and mortality of COVID‐19 by using publicly available databases. Results We found that a possible association between HLA‐A*02:01 and an increased risk for COVID‐19. HLA‐A*02:01 had a relatively lower capacity to present SARS‐CoV‐2 antigens compared with other frequent HLA class I molecules, HLA‐A*11:01 or HLA‐A*24:02. Conclusion This study suggests that individuals with HLA‐A*11:01 or HLA‐A*24:02 genotypes may generate efficiently T‐cell‐mediated antiviral responses to SARS‐CoV‐2 compared with HLA‐A*02:01. The differences in HLA genotypes may potentially alter the course of the disease and its transmission.

Accompanied by the growing clinical applications of immunotherapy in the treatment of cancer patients, development of novel therapeutic approaches to reverse the immune‐suppressive environment in cancer patients is eagerly anticipated, because the success of cancer immunotherapy is currently limited by immune‐suppressive effects in tumor‐bearing hosts. Interleukin (IL)‐6, a pleotropic proinflammatory cytokine, participates in tumor cell‐autonomous processes that are required for their survival and growth, and is therefore known as a poor prognostic factor in cancer patients. In addition, an emerging role of IL‐6 in modulating multiple functions of immune cells including T cells, dendritic cells, and macrophages is responsible for the dysfunction of innate and adaptive immunity against tumors. Therefore, the IL‐6‐targeting approach is of value as a promising strategy for desensitization and prevention of immune‐suppressive effects, and should be an effective treatment when combined with current immunotherapies. The aim of the present review is to discuss the immune‐suppressive aspects of IL‐6, notably with modification of T‐cell functions in cancer patients, and their relationship to anti‐tumor immune responses and cancer immunotherapy.

IL6 produced by tumor cells promotes their survival, conferring a poor prognosis in patients with cancer. IL6 also contributes to immunosuppression of CD4 þ T cell-mediated antitumor effects.In this study, we focused on the impact of IL6 trans-signaling mediated by soluble IL6 receptors (sIL6R) expressed in tumorbearing hosts. Higher levels of sIL6R circulating in blood were observed in tumor-bearing mice, whereas the systemic increase of sIL6R was not prominent in tumor-bearing mice with myeloid cellspecific conditional deletion of IL6R even when tumor cells produced sIL6R. Abundant sIL6R was released by CD11b þ cells from tumor-bearing mice but not tumor-free mice. Notably, IL6-mediated defects in Th1 differentiation, T-cell helper activity for tumorspecific CD8 þ T cells, and downstream antitumor effects were rescued by myeloid-specific deletion of sIL6R. Expression of the T-cell transcription factor c-Maf was upregulated in CD4 þ T cells primed in tumor-bearing mice in an IL6-dependent manner. Investigations with c-Maf loss-of-function T cells revealed that c-Maf activity was responsible for IL6/sIL6R-induced Th1 suppression and defective T-cell-mediated antitumor responses. In patients with cancer, myeloid cell-derived sIL6R was also possibly associated with Th1 suppression and c-Maf expression. Our results argued that increased expression of sIL6R from myeloid cells and subsequent cMaf induction were adverse events for counteracting tumor-specific Th1 generation. Overall, this work provides a mechanistic rationale for sIL6R targeting to improve the efficacy of T-cell-mediated cancer immunotherapy. Cancer Res; 77(9); 2279-91. Ó2017 AACR.