Abstract IA19: Myeloid cell control of tumor immunity

Abstract

Abstract While the success of T-cell checkpoint-targeted immunotherapies is predicated on the induction of an effector T-cell response against tumor antigens by potent antigen-presenting cells (APC), very little is known about the APC composition in human tumors during immunotherapy. APC form a diverse population of dendritic cells (DCs) and macrophages (macs) that share the capacity to capture and present cell-associated antigens to T cells and instruct the repertoire and effector versus regulatory function of T lymphocytes. Despite the key role of APC in tumor immunotherapy, targeting the APC compartment has proved difficult. This is because little is known about the APC molecular changes during tumor response or resistance to immunotherapy. In order to develop ways to modulate tumor APC and promote cancer immunity, we sought to gain a deeper understanding of the molecular and functional diversity of APC in human NSCLC. Using paired mass cytometry analysis of tumor/adjacent tissues, we recently identified major changes in APC and T-cell composition in early non-small lung cancer (NSCLC) lesions (Lavin et al., Cell 2017). More recently, we used cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) to further measure APC defects in the tumor lesions. CITE-seq analysis of the tumor lesions revealed profound alterations in tumor APC composition including a reduction of cross-presenting DC at the expense of monocyte-derived cells, which correlated with the presence of dysfunctional T cells compared to the adjacent tissue. Accordingly, we found that DC composition and molecular state controlled CD8+ T-cell accumulation at the tumor site and controlled tumor response to checkpoint blockade in preclinical models. Here, I will discuss the strategies we have developed to enhance DC functionality at the tumor site and the challenges that remain. Citation Format: Miriam Merad. Myeloid cell control of tumor immunity [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr IA19.