Abstract IA10: PMN-MDSC and neutrophils: Tale of two cells in cancer

Abstract

Abstract Myeloid cells are a critical component of the tumor microenvironment. In cancer, the myeloid compartment is dramatically affected, which is now considered as one of the major immunological hallmarks of cancer. Accumulation of immunosuppressive macrophages (MΦ), defective dendritic cells (DC) function and expansion of pathologically activated immune suppressive immature myeloid cells – myeloid-derived suppressor cells (MDSC) are major changes in the myeloid compartment in cancer. The total population of MDSC consists of three groups of cells: the most abundant (>75%) immature, pathologically activated neutrophils (PMN-MDSC); the less abundant population of pathologically activated monocytes – (M-MDSC). Tumor associated macrophages (TAM) and DCs can persist in tissues for a long time, whereas PMN-MDSC have short lifespan (< 48 hours) and are constantly replaced from bone marrow (BM). The role of MDSC in mouse tumor models is well established. In most of the studies PMN-MDSC were cells that expanded the most. In recent years, the clinical role of MDSC has emerged. Results showed positive correlation of MDSC in peripheral blood with cancer stage and tumor burden. In a meta-analysis, elevated MDSC in the circulation was found to be an independent indicator of poor outcomes in patients with solid tumors and predicting response to chemotherapy therapy, radiotherapy failure, and immunotherapy. It is widely accepted that the population of myeloid cells in cancer is heterogenic. It consists of cells able to exert antitumor and pro-tumorigenic activity. The nature of this heterogeneity is highly controversial. Some data suggested that PMN-MDSC in tumors may undergo polarization in situ, similar to that observed in TAM. Based on available data on the very short lifespan of MDSC in animal models and cancer patients as well as on functional data, we have postulated that at any given moment, myeloid cells in tissues are comprised of classically activated neutrophils (PMN) and monocytes, with pro-inflammatory and antitumor activity, and pathologically activated MDSC with potent immune suppressive and pro-tumorigenic activity. The balance between these cells defines the tumor microenvironment as immunosuppressive. This balance depends on the stage of cancer. It is equally plausible that in tissues, MDSC are present not in a binary state but in a range of functional states that are characterized by different markers and different functional activities. We will discuss evidence supporting this hypothesis. This question has a direct implication for cancer therapy. It is not clinically feasible to deplete the entire population of PMN and monocytes in cancer patients. However, if a specific group of functionally defined M-MDSC and PMN-MDSC is determined, then much more precise methods of therapeutic targeting could be developed. Potential approaches to such targeting are currently being investigated. Citation Format: Dmitry I. Gabrilovich. PMN-MDSC and neutrophils: Tale of two cells in cancer [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr IA10.