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Suppressing MDSC Recruitment to the Tumor Microenvironment by Antagonizing CXCR2 to Enhance the Efficacy of Immunotherapy.

ABSTRACT: Myeloid-derived suppressor cells (MDSCs) are a heterogenous population of cells derived from immature myeloid cells. These cells are often associated with poor responses to cancer therapy, including immunotherapy, in a variety of tumor types. The C-X-C chemokine receptor 2 (CXCR2) signaling axis plays a key role in the migration of immunosuppressive MDSCs into the tumor microenvironment (TME) and the pre-metastatic niche. MDSCs impede the efficacy of immunotherapy through a variety of mechanisms. Efforts to target MDSCs by blocking CXCR2 is an active area of research as a method for improving existing and novel immunotherapy strategies. As immunotherapies gain approval for a wider array of clinical indications, it will become even more important to understand the efficacy of CXCR2 inhibition in combating immunotherapy resistance at different stages of tumor progression.

SUBMITTER: Bullock K

PROVIDER: S-EPMC8699249 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Suppressing MDSC Recruitment to the Tumor Microenvironment by Antagonizing CXCR2 to Enhance the Efficacy of Immunotherapy.

Bullock Kennady K Richmond Ann A

Cancers 20211215 24

Myeloid-derived suppressor cells (MDSCs) are a heterogenous population of cells derived from immature myeloid cells. These cells are often associated with poor responses to cancer therapy, including immunotherapy, in a variety of tumor types. The C-X-C chemokine receptor 2 (CXCR2) signaling axis plays a key role in the migration of immunosuppressive MDSCs into the tumor microenvironment (TME) and the pre-metastatic niche. MDSCs impede the efficacy of immunotherapy through a variety of mechanisms ...[more]

PMID: 34944914

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Project description:Background: Pancreatic ductal adenocarcinoma (PDAC) is notorious for its profoundly immunosuppressive nature. The complex crosstalk between diverse immune cell types and heterogeneous tumor cell populations shapes this challenging tumor immune microenvironment (TIME). In this study, the role of transmembrane BAX inhibitor motif-containing 1 (TMBIM1) in modulating the TIME and its potential as a therapeutic target in PDAC were investigated. Methods: RNA sequencing was used to assess differential gene expression between PANC-1 cells with TMBIM1 knockdown and control cells. Single-cell RNA sequencing further validated the role of TMBIM1 in modulating the expression of CCL2 and PD-L1. Mechanistic insights were gained through chromatin immunoprecipitation, ELISA, real-time quantitative PCR, and flow cytometry experiments. To evaluate the impact of TMBIM1 on immune cell dynamics, we employed an in vitro chemotaxis assay and an in vivo C57BL/6J mouse xenograft model to examine CD8+ T-cell activation and myeloid-derived suppressor cell (MDSC) infiltration. Additionally, the therapeutic potential of TMBIM1 knockdown combined with anti-PD-1 antibody treatment was investigated in PDAC animal models. Results: TMBIM1 was significantly upregulated in pancreatic cancer tissues and cell lines, driving pancreatic cancer cell proliferation, growth, and migration both in vitro and in vivo. Elevated TMBIM1 expression induced high infiltration of MDSCs and fostered an immunosuppressive tumor microenvironment. Mechanistically, TMBIM1 binds to the transcription factor Y box binding protein 1 (YBX1), which in turn increases the affinity of YBX1 for the PD-L1 and CCL2 gene promoters. This interaction results in their upregulation, leading to increased MDSC infiltration, thereby facilitating the immunosuppressive TIME in PDAC. Notably, the combination of TMBIM1 knockdown with anti-PD-1 therapy had a more potent antitumor effect than anti-PD-1 therapy alone. Conclusions: Our study reveals that the TMBIM1/YBX1 axis is a key driver of immune evasion in PDAC and shapes the immunosuppressive TIME through the upregulation of CCL2 and PD-L1 expression. These findings highlight TMBIM1 as a potential therapeutic target to sensitize PDAC to immunotherapy.

Dataset Information

Suppressing MDSC Recruitment to the Tumor Microenvironment by Antagonizing CXCR2 to Enhance the Efficacy of Immunotherapy.

Publications

Suppressing MDSC Recruitment to the Tumor Microenvironment by Antagonizing CXCR2 to Enhance the Efficacy of Immunotherapy.

Similar Datasets

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