Regulation of myeloid-derived suppressor cell expansion by TRAF3 during chronic inflammation

Abstract Myeloid-derived suppressor cells (MDSCs) expand under pathological conditions and orchestrate the immunosuppressive and inflammatory network, and thus are recognized as a prime therapeutic target of human cancers and inflammatory diseases. In this study, we identified the tumor suppressor TRAF3 as a critical regulator of MDSC expansion. We found that myeloid cell-specific Traf3-deficient (M-Traf3−/−) mice exhibited MDSC hyperexpansion during chronic inflammation. Using mixed bone marrow chimeras, we demonstrated that TRAF3-mediated regulation of MDSC expansion involves cell-extrinsic mechanisms. To delineate the environmental factors that induce the aberrant expansion of MDSCs in M-Traf3−/− mice, we performed cytokine protein array analyses and in vivo neutralization experiments. Our results revealed that G-CSF is a major driver of MDSC hyperexpansion in M-Traf3−/− mice during chronic inflammation. Furthermore, we found that G-CSF was mainly produced by CCR4+ inflammatory monocytes and macrophages in mice during chronic inflammation. Taken together, our findings provide novel insights into the cellular and molecular mechanisms underlying TRAF3-mediated regulation of MDSC expansion, and open up new avenues for the development of MDSC-targeting therapeutics in disease conditions. This study was supported by the National Institutes of Health grant R21 AI128264 (P. Xie), a New Jersey Commission on Cancer Research (NJCCR) grant DCHS19CRF005 (P. Xie), a Pilot Award of Cancer Institute of New Jersey through Grant Number P30CA072720 from the National Cancer Institute (P. Xie), and a Busch Biomedical Grant (P. Xie).