Dataset Information

BRCA1 Insufficiency Induces a Hypersialylated Acidic Tumor Microenvironment That Promotes Metastasis and Immunotherapy Resistance.

ABSTRACT: Cancer metastasis is an extremely complex process affected by many factors. An acidic microenvironment can drive cancer cell migration toward blood vessels while also hampering immune cell activity. Here, we identified a mechanism mediated by sialyltransferases that induces an acidic tumor-permissive microenvironment (ATPME) in BRCA1-mutant and most BRCA1-low breast cancers. Hypersialylation mediated by ST8SIA4 perturbed the mammary epithelial bilayer structure and generated an ATPME and immunosuppressive microenvironment with increased PD-L1 and PD1 expressions. Mechanistically, BRCA1 deficiency increased expression of VEGFA and IL6 to activate TGFβ-ST8SIA4 signaling. High levels of ST8SIA4 led to accumulation of polysialic acid (PSA) on mammary epithelial membranes that facilitated escape of cancer cells from immunosurveillance, promoting metastasis and resistance to αPD1 treatment. The sialyltransferase inhibitor 3Fax-Peracetyl Neu5Ac neutralized the ATPME, sensitized cancers to immune checkpoint blockade by activating CD8 T cells, and inhibited tumor growth and metastasis. Together, these findings identify a potential therapeutic option for cancers with a high level of PSA.

Significance

BRCA1 deficiency generates an acidic microenvironment to promote cancer metastasis and immunotherapy resistance that can be reversed using a sialyltransferase inhibitor.

SUBMITTER: Shu X

PROVIDER: S-EPMC10391349 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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BRCA1 Insufficiency Induces a Hypersialylated Acidic Tumor Microenvironment That Promotes Metastasis and Immunotherapy Resistance.

Shu Xiaodong X Li Jianjie J Chan Un In UI Su Sek Man SM Shi Changxiang C Zhang Xin X An Tingting T Xu Jun J Mo Lihua L Liu Jianlin J Wang Yuqing Y Li Xiaoling X Deng Min M Lei Josh Haipeng JH Wang Chunfei C Tian Hao H Heng Sun S Shim Joong Sup JS Zhang Xuanjun X Dai Yunlu Y Yao Zhicheng Z Kuang Xiaying X Lin Ying Y Deng Chu-Xia CX Xu Xiaoling X

Cancer research 20230801 15

Cancer metastasis is an extremely complex process affected by many factors. An acidic microenvironment can drive cancer cell migration toward blood vessels while also hampering immune cell activity. Here, we identified a mechanism mediated by sialyltransferases that induces an acidic tumor-permissive microenvironment (ATPME) in BRCA1-mutant and most BRCA1-low breast cancers. Hypersialylation mediated by ST8SIA4 perturbed the mammary epithelial bilayer structure and generated an ATPME and immunos ...[more]

PMID: 37227919

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Project description:Background: Identifying biomarkers that predict immunotherapy efficacy and discovering new targets for combination therapies are critical elements for improving the prognosis of bladder cancer (BLCA) patients. Methods: Firstly, we explored the expression patterns of TBX3 in normal and pan-cancer tissues and the correlation between TBX3 and the immune microenvironment using data from multiple public databases. Then, we combined various techniques, including bulk RNA sequencing, single-cell RNA sequencing, high-throughput cytokine arrays, functional experiments, ProcartaPlex multiplex immunoassays and TissueFAXS panoramic tissue quantification assays, to demonstrate that TBX3 shapes an immunosuppressive tumor microenvironment (TME) in BLCA. Results: We identified TBX3 as a key factor associated with the immunosuppressive microenvironment in BLCA through a systematic multi-omics analysis. We found that TBX3 is primarily expressed in malignant cells, where TBX3high tumor cells increase the secretion of TGFβ1, which promotes the infiltration of cancer-associated fibroblasts (CAFs), thereby forming an immunosuppressive microenvironment. We further demonstrated that TBX3 enhances TGFβ1 expression by binding to the TGFβ1 promoter, and blocking TGFβ1 counteracts the immunosuppressive effects of TBX3. Moreover, TBX3 reduced the cancer-killing efficiency of CD8+ T cells by decreasing the proportion of GZMB+ CD8+ T cells, and knocking down TBX3 combined with anti-PD-1 treatment increased CD8+ T cell infiltration and reduced CAFs in vivo. We also validated the inverse relationship between TBX3+ malignant cells and CD8+ T cells and the positive relationship with CAFs in tissue microarrays. Lastly, we found that TBX3 predicted immunotherapy efficacy in our real-world immunotherapy cohort and multiple public cohorts. Conclusion: In summary, TBX3 promotes BLCA progression and immunotherapy resistance by inducing an immunosuppressive microenvironment, and targeting TBX3 could enhance the efficacy of immunotherapy for BLCA.

Dataset Information

BRCA1 Insufficiency Induces a Hypersialylated Acidic Tumor Microenvironment That Promotes Metastasis and Immunotherapy Resistance.

Significance

Publications

BRCA1 Insufficiency Induces a Hypersialylated Acidic Tumor Microenvironment That Promotes Metastasis and Immunotherapy Resistance.

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