Poor clinical outcomes and immunoevasive contexture in CXCL13+CD8+ T cells enriched gastric cancer patients.
As an adverse survival prognosticator, chemokine (C-X-C motif) ligand 13 (CXCL13) has been studied in several types of malignancies. The secretion and physiological roles of CXCL13 in follicular helper T cells (TFH) cells have been well described, while the clinical significance of CD8+ tumor-infiltrating lymphocytes (TILs)-associated CXCL13 remains unknown. This study aims to investigate the clinical significance of CXCL13+CD8+ T cells in survival and chemotherapeutic responsiveness prediction in gastric cancer. In this study, 440 patients enrolled from Zhongshan Hospital with tumor microarray (TMA) specimens were randomly divided into testing set (n = 220) and validation set (n = 220) for analysis. CXCL13+CD8+ T cells were detected by multicolor immunohistochemistry. Fresh tumor tissue samples from another 60 gastric cancer patients were collected to detect CXCL13+CD8+ T cells functional status by flow cytometry (FCM). We found that high intratumoral CXCL13+CD8+ T cells infiltration predicted poor overall survival and inferior chemotherapeutic responsiveness in gastric cancer. CXCL13+CD8+T cells were associated with immunoevasive contexture with increased regulatory T (Treg) cells and dysfunctional cytotoxic T lymphocytes (CTLs). Moreover, the combinational analysis of CXCL13+CD8+ T cells and CD8+ T cells infiltration stratified patients into distinct risk groups with different clinical outcomes and chemotherapeutic responsiveness. Conclusively, intratumoral CXCL13+CD8+ T cells infiltration could be an independent prognostic and predictive marker for gastric cancer patients. CXCL13+CD8+ T cells represented an exhausted CD8+ T cell subset, and might be a potential immunotherapeutic target in gastric cancer.
Jin K
，Cao Y
，Gu Y
，Fang H
，Fei Y
，Wang J
，Liu X
，Lv K
，He X
，Lin C
，Liu H
，Li H
，He H
，Li R
，Zhang H
，Xu J
... -
《OncoImmunology》
Comprehensive Multi-Omics Identification of Interferon-γ Response Characteristics Reveals That RBCK1 Regulates the Immunosuppressive Microenvironment of Renal Cell Carcinoma.
Interferon-gamma (IFN-γ) has a complex role in modulating the tumor microenvironment (TME) during renal cell carcinoma (RCC) development. To define the role of IFN-γ response genes in RCC progression, we characterized the differential gene expression, prognostic implications, and DNA variation profiles of selected IFN-γ response signatures, which exhibited a significant hazard ratio for the overall survival (OS) and progression-free survival (PFS) of papillary, chromophobia, and clear cell RCC (ccRCC) patients (n = 944). Prognostic nomograms were constructed to predict the outcomes for ccRCC patients, highlighting the prognostic implications of RANBP2-type and C3HC4-type zinc finger containing 1 (RBCK1). Interestingly, large-scale pan-cancer samples (n = 12,521) and three single-cell RNA datasets revealed that RBCK1 showed markedly differential expression between cancer and normal tissues and significantly correlated with tumor-infiltrating immune cells, tumor purity, and immune checkpoint molecules, such as PD-L1, CTLA-4, LAG-3, and TIGIT in pan-cancer samples. Notably, the TIDE score was significantly higher in the RBCK1high group compared with the RBCK1low group in both ccRCC and RCC cohorts. Besides, immunohistochemistry staining showed significantly elevated RBCK1 expression in tumors (n = 50) compared with kidney samples (n = 40) from a real-world cohort, Fudan University Shanghai Cancer Center (FUSCC, Shanghai). After RBCK1 expression was confirmed in ccRCC, we found a significantly decreased number of infiltrating CD4+ T cells, CD4+ FOXP3+ Treg cells, M1 macrophages, and CD56bight/dim NK cells in the immune-cold RBCK1high group. In addition to the distinct heterogeneous immune microenvironment, the increased expression of RBCK1 predicted a prominently worse prognosis than the RBCK1low group for 232 ccRCC patients in the FUSCC proteomic cohort. Furthermore, after transfected with siRNA in human ccRCC cells, extraordinarily decreased cell proliferation, migration capacities, and prominently elevated apoptosis tumor cell proportion were found in the siRNA groups compared with the negative control group. In conclusion, this study identified IFN-γ response clusters, which might be used to improve the prognostic accuracy of immune contexture in the ccRCC microenvironment. Immune-cold RBCK1high patients have pro-tumorigenic immune infiltration and significantly worse outcomes than RBCK1low patients based on results from multi-omics to real-world data. Our discovery of novel independent prognostic indicators for RCC highlights the association between tumor alterations and immune phenotype.
Xu W
，Tao J
，Zhu W
，Liu W
，Anwaier A
，Tian X
，Su J
，Shi G
，Huang H
，Wei G
，Li C
，Qu Y
，Zhang H
，Ye D
... -
《Frontiers in Immunology》
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》
ResearchGate
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钛学术
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