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B7-H5 blockade enhances CD8⁺ T-cell-mediated antitumor immunity in colorectal cancer.

ABSTRACT: Negative immune checkpoint blockade immunotherapy has shown potential for multiple malignancies including colorectal cancer (CRC). B7-H5, a novel negative immune checkpoint regulator, is highly expressed in tumor tissues and promotes tumor immune escape. However, the clinical significance of B7-H5 expression in CRC and the role of B7-H5 in the tumor microenvironment (TME) has not been fully clarified. In this study, we observed that high B7-H5 expression in CRC tissues was significantly correlated with the lymph node involvement, AJCC stage, and survival of CRC patients. A significant inverse correlation was also observed between B7-H5 expression and CD8⁺ T-cell infiltration in CRC tissues. Kaplan-Meier analysis showed that patients with high B7-H5 expression and low CD8⁺ T-cell infiltration had the worst prognosis in our cohort of CRC patients. Remarkably, both high B7-H5 expression and low CD8⁺ T infiltration were risk factors for overall survival. Additionally, B7-H5 blockade using a B7-H5 monoclonal antibody (B7-H5 mAb) effectively suppressed the growth of MC38 colon cancer tumors by enhancing the infiltration and Granzyme B production of CD8⁺ T cells. Importantly, the depletion of CD8⁺ T cells obviously abolished the antitumor effect of B7-H5 blockade in the MC38 tumors. In sum, our findings suggest that B7-H5 may be a valuably prognostic marker for CRC and a potential target for CRC immunotherapy.

SUBMITTER: Wang J

PROVIDER: S-EPMC8449782 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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B7-H5 blockade enhances CD8<sup>+</sup> T-cell-mediated antitumor immunity in colorectal cancer.

Wang Jiayu J Wu Hongya H Chen Yanjun Y Zhu Jinghan J Sun Linqing L Li Juntao J Yao Zhendong Z Chen Yuqi Y Zhang Xueguang X Xia Suhua S Chen Weichang W Shi Tongguo T

Cell death discovery 20210918 1

Negative immune checkpoint blockade immunotherapy has shown potential for multiple malignancies including colorectal cancer (CRC). B7-H5, a novel negative immune checkpoint regulator, is highly expressed in tumor tissues and promotes tumor immune escape. However, the clinical significance of B7-H5 expression in CRC and the role of B7-H5 in the tumor microenvironment (TME) has not been fully clarified. In this study, we observed that high B7-H5 expression in CRC tissues was significantly correlat ...[more]

PMID: 34537815

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Project description:BackgroundNon-small cell lung cancer (NSCLC) is a highly aggressive type of lung cancer with poor responses to traditional therapies such as surgery, radiotherapy, and chemotherapy. While immunotherapy has become an effective approach for treating multiple types of cancer, solid tumors frequently exhibit immune escape through various mechanisms, including downregulation of MHC I expression. However, whether the upregulation of MHC I expression can improve the immunotherapeutic effect on NSCLC remains unexplored. Suberoylanilide hydroxamic acid (SAHA) is a potent histone deacetylase (HDAC) inhibitor that has been applied clinically to treat lymphoma, but a high dose of SAHA kills tumor cells and normal cells without preference. Here, we report that low-dose SAHA enhances CD8+ T cell-mediated antitumor immunity by upregulating MHC I expression in NSCLC cells.MethodsFlow cytometric analysis, quantitative real-time PCR and western blot were used to analyze the expression of MHC I, STAT1 and Smad2/3 in both human and mouse NSCLC cell lines after SAHA treatment. The nuclear translocation of phosphorylated STAT1 and Smad2/3 was investigated by western blot and immunofluorescence staining. The mechanisms underlying STAT1 and Smad2/3 upregulation were analyzed through database searches and chromatin immunoprecipitation-qPCR. Finally, we assessed the antitumor effect of specific CD8+ T cells with SAHA treatment in vivo and in vitro.ResultsWe showed that low-dose SAHA upregulated the expression of MHC I in NSCLC cell lines without affecting cell viability. We also provided evidence that high levels of MHC I induced by SAHA promoted the activation, proliferation, and cytotoxicity of specific CD8+ T cells in mouse models. Mechanistically, low-dose SAHA increased the levels of H3K9ac and H3K27ac in the promoters of the STAT1, Smad2 and Smad3 genes in NSCLC cells by inhibiting HDAC activity, resulting in elevated expression levels of STAT1, Smad2 and Smad3. The nuclear translocation of phosphorylated STAT1 and Smad2/3 markedly upregulated the expression of MHC I in NSCLC cells.ConclusionsLow-dose SAHA enhances CD8+ T cell-mediated antitumor immunity by boosting MHC I expression in NSCLC cells. Thus, we revealed a key mechanism of SAHA-mediated enhanced antitumor immunity, providing insights into a novel immunotherapy strategy for NSCLC.

Dataset Information

B7-H5 blockade enhances CD8⁺ T-cell-mediated antitumor immunity in colorectal cancer.

Publications

B7-H5 blockade enhances CD8<sup>+</sup> T-cell-mediated antitumor immunity in colorectal cancer.

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Dataset Information

B7-H5 blockade enhances CD8+ T-cell-mediated antitumor immunity in colorectal cancer.

Publications

B7-H5 blockade enhances CD8<sup>+</sup> T-cell-mediated antitumor immunity in colorectal cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

B7-H5 blockade enhances CD8⁺ T-cell-mediated antitumor immunity in colorectal cancer.