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.
Approximately one million veterans aged 50 and older will develop colorectal cancer over the remainder of their lives and nearly 433,000 will die from it. On a national basis, the relative five year survival with colorectal cancer was estimated at only approximately 40% among veterans, substantially lower than the 60% survival rate among the general population. MDSC accumulation is a hallmark of human colorectal cancer and PD-L1 is a major immune suppressive ligand of MDSCs. Therefore, it is critical to study PD- L1 expression regulation and functions in MDSCs in human colorectal cancer patients. The proposed studies have the potential to determine the role of PD-L1 in colon cancer immune evasion and will provide the basis for molecular mechanism-based therapy to suppress MDSCs-dependent colon cancer progression.
