Abstract 4734: Suppressive myeloid cells of the solid tumor microenvironment enhance regulatory T cell function and differentially affect CAR-T cell function
Authors: Rivas Charlotte H. , Cole Anna , Rooney Cliona M. , Parihar Robin 
Published: August 2018

Immunotherapy with tumor-directed immune cells, such as chimeric antigen receptor-bearing T (CAR-T) cells, have shown great promise. Indeed, CAR-T cells directed against leukemia antigens such as CD19 have produced impressive complete responses even in relapsed disease patients. In contrast, CAR-T cells directed against solid tumor have produced very few durable clinical responses. This may be, in part, due to the suppressive immune microenvironment of solid tumors that inhibits the anti-tumor activity of endogenous and CAR-T cells. Myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs) and inhibitory macrophages (M2s) are recruited by tumor-derived factors, and contribute to the immunosuppressive tumor microenvironment (TME) by secreting suppressive cytokines, expressing inhibitory ligands, and promoting tumor neovascularization. However, the contribution of each of these components to suppressing engineered cellular therapies has not been well defined. In order to design more effective cellular therapies for solid tumors, it is imperative that we understand TME-mediated immune suppression of human CAR-T cells. Therefore, the objective of this study was to evaluate the individual contribution of MDSCs, Tregs, and M2s to the suppressive TME and their ability to modulate CAR-T function. We hypothesized that MDSCs, Tregs, and M2s would inhibit GD2.CAR-T homing and proliferation at tumor sites, leading to decreased activity and tumor progression. To understand the individual contributions of these suppressive cells to inhibition of CAR-T cells, we developed a unique TME model in which human neuroblastoma tumor cells were co-inoculated subcutaneously with MDSCs, Tregs, or M2s in immunocompromised mice and then treated with GD2 neuroblastoma antigen-specific CAR-T cells. We found that while all three cell types decreased GD2.CAR-T cell-mediated tumor control in vivo, only MDSCs and M2s inhibited CAR-T homing and expansion at tumor sites. To investigate cross-talk between these suppressive cells, we assessed the phenotype and suppressive activity of MDSCs, Tregs, and M2 on autologous CAR-T cells after exposure to the other suppressive cell types. We found that the suppressive function of M2s increased by 30% after exposure to Tregs. Similarly, Treg suppressive function increased by 26% after exposure to M2s. Both M2 and Treg suppressive functions were enhanced in the presence of MDSCs. Our results suggest a potential cross-talk between suppressive cells of the TME and distinct roles in important aspects of CAR-T cell function, including homing and killing. Future studies in our lab aim to further understand the differential roles of these cells in regulating CAR-T cell function within the TME that will inform new approaches to engineer effective adoptive T-cell therapies.

Citation Format: Charlotte H. Rivas, Anna Cole, Cliona M. Rooney, Robin Parihar. Suppressive myeloid cells of the solid tumor microenvironment enhance regulatory T cell function and differentially affect CAR-T cell function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4734.