Type I Interferon Regulation of PD-L1 Expression and Function in MDSCs

Project: Research project

Project Details

Description

Project Abstract Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells (IMCs). Under physiological conditions, IMCs quickly differentiate into mature granulocytes, macrophages or dendritic cells. By contrast, under pathological conditions, a partial block of IMC differentiation into mature myeloid cells results in the expansion and activation of this population. In human cancer patients, massive accumulation of MDSCs is a hallmark of cancer progression. One key function of MDSCs is to inhibit activation of cytotoxic T lymphocytes (CTLs) through multiple suppressive mechanisms. PD-L1 has emerged as a new immune suppressive factor of MDSCs. However, the function of MDSC-expressed PD-L1 in suppression of CTL activation in the tumor microenvironment is currently controversial. Our preliminary studies determined for the first time that type I IFNs regulate constitutive PD-L1 expression in MDSCs in an autocrine manner. We further determined that IFNAR1 controls PD-L1 expression level in MDSCs in the tumor microenvironment. Therefore, type I IFNs might play a dominant role over IFN? in up-regulating PD-L1 expression in MDSCs in the tumor microenvironment, which remains to be determined. Our central hypothesis is that type I IFNs regulate PD-L1 expression in tumor-infiltrating MDSCs and both tumor-expressed and MDSC-expressed PD-L1 contributes to CTL suppression and tumor immune evasion in human colon cancer. The objectives are: 1) elucidate the molecular mechanism underlying PD-L1 expression regulation by type I IFNs in MDSCs; 2) Determine the relative contributions of tumor-expressed and MDSC-expressed PD-L1 in suppression of CTL activation and tumor immune evasion; and 3) Test the hypothesis that type I IFN regulates PD-L1 expression in MDSCs in human colon cancer patients. Successful completion of the proposed studies will determine the function of MDSC-expressed PD-L1 in immune suppression and tumor immune evasion in human colorectal cancer patients and identify novel molecular target to enhance the efficacy of checkpoint inhibitor immunotherapy in human colon cancer.
StatusNot started

Funding

  • National Institutes of Health

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