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Importance of myeloid derived suppressor cells in cancer from a biomarker perspective.

ABSTRACT: Myeloid derived suppressor cells (MDSC) are a heterogenous population of immature myeloid cells that accumulate in tumor bearing host and migrate to lymphoid organs and tumor tissues. This process is controlled by a set of defined pro-inflammatory cytokines and chemokines, which are upregulated in malignancies. MDSC have strong immunosuppressive potential and constitute a major component of the tumor microenvironment (TME). Tumor cells take advantage of the suppressive mechanisms of MDSC to establish an immunosuppressive TME which inhibits antitumor immune responses thereby promoting cancer progression. An immunosuppressive TME acts as a significant barrier to immunotherapeutic interventions. Pre-clinical and clinical studies have demonstrated that enrichment and activation of MDSC is correlated with tumor progression, recurrence and metastasis. In this review we discuss the potential impact of MDSC on tumor progression and its role as a biomarker of prognostic significance in cancer with a special focus on hepatocellular cancer (HCC).

SUBMITTER: Kalathil SG

PROVIDER: S-EPMC9204650 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Importance of myeloid derived suppressor cells in cancer from a biomarker perspective.

Kalathil Suresh Gopi SG Thanavala Yasmin Y

Cellular immunology 20201231

Myeloid derived suppressor cells (MDSC) are a heterogenous population of immature myeloid cells that accumulate in tumor bearing host and migrate to lymphoid organs and tumor tissues. This process is controlled by a set of defined pro-inflammatory cytokines and chemokines, which are upregulated in malignancies. MDSC have strong immunosuppressive potential and constitute a major component of the tumor microenvironment (TME). Tumor cells take advantage of the suppressive mechanisms of MDSC to esta ...[more]

PMID: 33445053

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Project description:BackgroundEmerging evidences suggest that aberrant metabolites contributes to the immunosuppressive microenvironment that leads to cancer immune evasion. Among tumor immunosuppressive cells, myeloid-derived suppressor cells (MDSCs) are pathologically activated and extremely immunosuppressive, which are closely associated with poor clinical outcomes of cancer patients. However, the correlation between MDSCs mediated immunosuppression and particular cancer metabolism remained elusive.MethodsSpontaneous lung adenocarcinoma and subcutaneous mouse tumor models, gas chromatography-mass spectrometry (GC-MS) and immunofluorescence assay of patient-derived lung adenocarcinoma tissues, and flow cytometry, RNA sequencing and Western blotting of immune cells, were utilized.ResultsMetabolite profiling revealed a significant accumulation of acetic acids in tumor tissues from both patients and mouse model, which contribute to immune suppression and cancer progression significantly through free fatty acid receptor 2 (FFAR2). Furthermore, FFAR2 is highly expressed in the myeloid-derived suppressor cells (MDSCs) from the tumor of lung adenocarcinoma (LUAD) patients which is greatly associated with poor prognosis. Surprisingly, whole or myeloid Ffar2 gene deletion markedly inhibited urethane-induced lung carcinogenesis and syngeneic tumor growth with reduced MDSCs and increased CD8+ T cell infiltration. Mechanistically, FFAR2 deficiency in MDSCs significantly reduced the expression of Arg1 through Gαq/Calcium/PPAR-γ axis, which eliminated T cell dysfunction through relieving L-Arginine consumption in tumor microenvironment. Therefore, replenishment of L-Arginine or inhibition to PPAR-γ restored acetic acids/FFAR2 mediated suppression to T cells significantly. Finally, FFAR2 inhibition overcame resistance to immune checkpoint blockade through enhancing the recruitment and cytotoxicity of tumor-infiltrating T cells.ConclusionAltogether, our results demonstrate that the acetic acids/FFAR2 axis enhances MDSCs mediated immunosuppression through Gαq/calcium/PPAR-γ/Arg1 signaling pathway, thus contributing to cancer progression. Therefore, FFAR2 may serve as a potential new target to eliminate pathologically activated MDSCs and reverse immunosuppressive tumor microenvironment, which has great potential in improving clinical outcomes of cancer immunotherapy.

Dataset Information

Importance of myeloid derived suppressor cells in cancer from a biomarker perspective.

Publications

Importance of myeloid derived suppressor cells in cancer from a biomarker perspective.

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