Intratumoral TIGIT(+) CD8(+) T-cell infiltration determines poor prognosis and immune evasion in patients with muscle-invasive bladder cancer.

T-cell immunoglobulin and ITIM domain (TIGIT) is identified as a novel checkpoint receptor that can facilitate immune escape via mediating T-cell exhaustion in tumors. However, the clinical significance and immune contexture correlation of intratumoral TIGIT+ CD8+ T-cells remain to be further explored in muscle-invasive bladder cancer (MIBC). 259 patients with MIBC from two clinical centers (Zhongshan Hospital, n=141; Shanghai Cancer Center, n=118) were analyzed to evaluate the prognostic value and immune contexture association of TIGIT+ CD8+ T-cells through immunohistochemistry. Fresh tumor tissue samples from 26 patients with MIBC were examined to discover the phenotype of this CD8 subpopulation by flow cytometry. High infiltration of intratumoral TIGIT+ CD8+ T-cells predicted poor overall survival (OS) and recurrence-free survival (RFS) in MIBC. For patients with stage II MIBC with low infiltration of TIGIT+ CD8+ cells, adjuvant chemotherapy (ACT) could significantly prolong their OS and RFS. Intratumoral TIGIT+ CD8+ T-cell abundance was correlated with impaired CD8+ T-cell cytotoxicity and exhibited production of immunosuppressive cytokine IL-10. Further analysis of tumor-infiltrating immune cell landscape revealed TIGIT+ CD8+ T-cells were associated with suppressive immune contexture, including Th2 cells, regulatory T-cells, mast cells and neutrophils. Intratumoral TIGIT+ CD8+ T-cell abundance could serve as an independent prognosticator for clinical outcome and a predictive biomarker for inferior ACT responsiveness. Intratumoral TIGIT+ CD8+ T-cell abundance correlated with dampened CD8+ T-cell antitumor immunity and immunosuppressive contexture abundance, highlighting a tumor-promoting role of TIGIT+ CD8+ T-cells.

Liu Z ，Zhou Q ，Wang Z ，Zhang H ，Zeng H ，Huang Q ，Chen Y ，Jiang W ，Lin Z ，Qu Y ，Xiong Y ，Bai Q ，Xia Y ，Wang Y ，Liu L ，Zhu Y ，Xu L ，Dai B ，Guo J ，Wang J ，Chang Y ，Zhang W ... -  《Journal for ImmunoTherapy of Cancer》

Intratumoral CXCL13(+)CD8(+)T cell infiltration determines poor clinical outcomes and immunoevasive contexture in patients with clear cell renal cell carcinoma.

Dai S ，Zeng H ，Liu Z ，Jin K ，Jiang W ，Wang Z ，Lin Z ，Xiong Y ，Wang J ，Chang Y ，Bai Q ，Xia Y ，Liu L ，Zhu Y ，Xu L ，Qu Y ，Guo J ，Xu J ... -  《Journal for ImmunoTherapy of Cancer》

Poor clinical outcomes and immunoevasive contexture in interleukin-9 abundant muscle-invasive bladder cancer.

Chemotherapy and immunotherapy yield survival benefits for muscle-invasive bladder cancer (MIBC) patients, in which tumor microenvironment has been found to exert crucial roles through tipping the balance between antitumor immunity and immune evasion. Our study aims to explore the clinical significance and therapeutic role of intratumoral interleukin-9-producing cells (IL-9+ cells) in MIBC. Two hundred fifty-nine MIBC patients from two independent clinic centers were utilized for retrospective analysis in the study. Sixty-five fresh MIBC tumor tissues were used to evaluate the infiltration and function of immune cells via flow cytometry and ex vivo intervention experiments. Three hundred ninety-one MIBC patients of The Cancer Genome Atlas were applied for bioinformatics analysis. It was found that patients with high IL-9+ cells infiltration had worse overall survival and relapse-free survival. pT2 patients with low IL-9+ cells infiltration could benefit more from adjuvant chemotherapy (ACT). IL-9+ cells infiltration was correlated with decreased expression of granzyme B from CD8+ T cells and natural killer (NK) cells and perforin from CD8+ T cells, while blockade of IL-9 reactivated the antitumor capacity of both cells leading to tumor regression. Furthermore, IL-9+ cells infiltration could be a biomarker for predicting anti-PD-1 efficacy. In conclusion, IL-9+ cells infiltration could be applied as an independent prognosticator for clinical outcome and ACT/anti-PD-1 effectiveness. IL-9+ cells infiltration diminished the cytotoxicity of CD8+ T cells and NK cells resulting in tumor immune evasion, and thus targeting IL-9 could be a potential therapeutic strategy for MIBC.

Zhou Q ，Zhang H ，Wang Z ，Zeng H ，Liu Z ，Huang Q ，Lin Z ，Qu Y ，Xiong Y ，Wang J ，Chang Y ，Bai Q ，Xia Y ，Wang Y ，Liu L ，Dai B ，Guo J ，Zhu Y ，Xu L ，Xu J ... -  《-》

Intratumoral IL22-producing cells define immunoevasive subtype muscle-invasive bladder cancer with poor prognosis and superior nivolumab responses.

Our previous researches have identified immunoevasive subtype muscle-invasive bladder cancer (MIBC) characterized with immune cells infiltration patterns. Our study explored the clinical significance, immunoregulatory role and therapeutic value of intratumoral IL22-producing cells in MIBC. Two hundred and fifty-nine formalin-fixed paraffin-embedded MIBC samples and 83 freshly resected MIBC tissues and 391 TCGA MIBC samples were retrospectively evaluated. Immunohistochemistry and flow cytometry were applied to identify immune cell infiltration and functional status. In vitro intervention studies were to test the therapeutic and predictive potential of IL22+ cells. Our data revealed patients with high IL22+ cells infiltration suffered poor overall survival and recurrence-free survival in both training and validation cohorts. Only pT2 patients of combined cohort with low IL22+ cells infiltration gained survival benefits from adjuvant chemotherapy (ACT) significantly. Besides, immune contexture featured with increased pro-tumor cells and immunosuppressive cytokines was identified in patients with high IL22+ cells density. The expression pattern of exhausted and effector markers in CD8+ T cells from high IL22+ cells subgroup indicated their dysfunctional status. Importantly, nivolumab showed tumor-killing efficacy in tumors with high IL22+ cells infiltration, and immunosuppressive contexture with CD8+ T cells exhaustion was abrogated in tumors treated with anti-IL22 antibody. In summary, IL22+ cells infiltration determined immunosuppressive contexture with CD8+ T cell dysfunction. Tumor-infiltrating IL22+ cells could be used as an independent marker to predict prognosis and ACT responses. IL22+ cells infiltration possessed the potential to be a favorable predictor for nivolumab application and IL22 blockade could be a novel therapeutic strategy in MIBC.

Zeng H ，Liu Z ，Wang Z ，Zhou Q ，Qi Y ，Chen Y ，Chen L ，Zhang P ，Wang J ，Chang Y ，Bai Q ，Xia Y ，Wang Y ，Liu L ，Zhu Y ，Dai B ，Guo J ，Xu L ，Zhang W ，Xu J ... -  《-》

Immune inactivation by VISTA predicts clinical outcome and therapeutic benefit in muscle-invasive bladder cancer.

V domain Immunoglobulin suppressor of T cell activation (VISTA) has been proved to be a novel immune checkpoint molecule that positively regulates T cell infiltration in several malignancies. However, the clinical impact of VISTA on muscle-invasive bladder cancer (MIBC) patients remains relatively obscure. This study enrolled 135 MIBC patients from Zhongshan Hospital (ZSHS) and 391 patients from The Cancer Genome Atlas (TCGA) to examine the VISTA expression and immune contexture based on immunohistochemistry (IHC) staining and CIBERSORT algorithm. Additionally, IMvigor210 Cohort included 195 bladder-derived urothelial carcinoma patients to evaluate the efficacy of immunotherapy. Kaplan-Meier curve and Cox regression analyses were conducted to assess clinical outcomes. MIBC patients with high VISTA+ immune cells (ICs) possessed poor overall survival and inferior therapeutic responsiveness to adjuvant chemotherapy (ACT), but superior responsiveness to PD-L1 inhibitor. VISTA+ ICs infiltration shaped an immunoevasive context featured by regulatory T cells (Tregs), M2 macrophages, mast cells and exhausted CD8+ T cells infiltration, with increased interleukin 10 (IL-10), transforming growth factor-β (TGF-β) and interferon-γ (IFN-γ), but also elevated T-cell immunoglobulin mucin-3 (TIM-3), lymphocyte activation gene 3 (LAG-3) and T-cell immunoglobulin and ITIM domain (TIGIT), which was also mainly presented in basal-squamous and luminal-infiltrated subtypes of MIBC. VISTA+ ICs infiltration could be an independent predictor to identify poor prognosis and therapeutic responses (PD-L1 blockade and ACT) in MIBC patients, which was associated with immunoevasive contexture. The novel immune checkpoint VISTA might be utilized as a candidate treatment biomarker in MIBC patients.

Li W ，Liu Z ，Jin K ，Shao F ，Zeng H ，Wang Y ，Zhu Y ，Xu L ，Wang Z ，Chang Y ，Zhang W ... -  《BMC CANCER》