Abstract 3611: Determining the regulation and role of mreg DC in tumor immunity

Abstract

Abstract Therapeutic immunity against tumors is mainly determined by effector T cells. However, T cells are educated by antigen presenting cells, particularly dendritic cells (DC), that control their differentiation into effector T cells able to eliminate target tumor cells. While most studies focused on understanding T cell features leading to antitumor immunity, little is known about DC determinants required to promote effective antitumor T cell function. Yet several studies are revealing that high DC content in tumor lesions correlate with improved tumor outcome. To identify molecular program that modulate DC functionality in tissues we have profiled tumor-associated DC in mice and tumor lesions. We identified a DC molecular program that was shared between mice and human tumors that included maturation genes associated with T cell simulation and migration to the LN (Cd40, Cd80, Fscn, Ccr7), but also genes associated with immunoregulation (Socs1, Socs2, Socs3, Cd200, Pd-l1, Pd-l2, Fasl), we named mregDC (Maier et al., Nature 2020). We also found that mregDC molecular state is induced in DC1 and DC2 upon capture of tumor debris leading to hypothesize that the mregDC state identifies antigen-charged DC that migrate to lymphoid structures, including tertiary lymphoid structures and tumor draining lymph nodes to modulate tumor specific T cell immune responses. While the role of DC in the draining LN has been established the exact role played by DC in the tumor microenvironment (TME) remains unclear. To explore this question, we used multiplex imaging and spatial transcriptomics platforms to identify the distribution and spatial interactions of DC1, DC2 and mregDC within the TME of human NSCLC and HCC lesions during treatment with PD-1 blockade. We found that mregDC accumulate within the tertiary lymphoid structures together with activated T cell and B cell programs. We are continuing to generate additional data on mregDC interactions in human tumors tissues that respond or resist PD-1 blockade and should be able to provide additional information at the time of the meeting. Citation Format: Raphael Mattiuz, Nima Assad, Pauline Hamon, Assaf Magen, Jessica Le Berichel, Miriam Merad. Determining the regulation and role of mreg DC in tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3611.