Project Summary The prominent change in the myeloid compartment in cancer is the expansion of pathologically activated immature myeloid cells with the potent ability to suppress immune responses – myeloid-derived suppressor cells (MDSC). In tumor-bearing mice, the total population of MDSC consists of three groups of cells: the most abundant (>75%) immature, pathologically activated neutrophils (PMN-MDSC); less abundant (<20%) population of pathologically activated monocytes (M-MDSC); and small (<5%) population of early myeloid precursors. In the tumor microenvironment MDSC are more immunosuppressive than in peripheral lymphoid organ. However, the mechanism of this phenomenon remains rather elusive. The gaps in our knowledge is in understanding the mechanisms regulating the function of MDSC in tumors and specific requirements for their targeting. In this proposal we will test the hypothesis that there are distinct populations of MDSC in tumors. These populations can be defined by specific markers and most importantly, have different sensitivity to ferroptotic cell death which determines their functional activity. We will test the concept that targeting ferroptosis in PMN-MDSC in cancer may have functional consequences for immune responses. The goal of this project is to uncover the mechanisms regulating myeloid cell function in tumors and to develop novel approaches to the regulation of immune responses in cancer. We propose the following Specific Aims: (1) To identify the mechanism of ferroptosis-mediated immune suppression induced by PMN-MDSC in tumors; and (2) To investigate therapeutic potential of targeting ferroptosis in PMN-MDSC.

Narrative This proposal addresses in preclinical setting an important clinical problem – tumor escape from immune therapy. We will investigate the basic mechanism of this phenomenon associated with the induction of ferroptosis, a program of regulated cell death. We will test this novel mechanism and its correction in relevant mouse models and determine its clinical relevance using de-identified samples from patients with lung, colon, and pancreatic cancer.