CD8 T-cell-mediated antitumor immunity is required for the control and elimination of tumors. However, tumors are able to overcome immune response resulting in immunosuppression, tumor growth, and metastatic spread. CD8 T-cells are controlled through a homeostatic network of positive and negative feedback loops. These negative signals are exploited by the tumor and associated suppressive cell populations in the tumor microenvironment. Immunotherapies targeted to receptors that control these negative signals, termed immune checkpoint inhibitors, have provided robust and durable responses to a number of cancers. Unfortunately, only a subset of patients will respond to current immunotherapies. This is due to the accruement of suppressive and inhibitory mechanisms employed by the tumor and its microenvironment. These include expression of inhibitory ligands, release of immune-suppressive factors, and the recruitment of suppressive cell populations. Furthermore, the administration of immune checkpoint inhibitors can enhance tumor acquisition of a more suppressive phenotype, diminishing immune responses through additional inhibitory pathways. We therefore propose that further CD8 T-cell-intrinsic negative regulators most likely exist, which can be targeted to improve antitumor responses. Here, we have used functional genomic approaches to identify pathways that can be targeted to advance anti-tumor responses, either in combination with anti-PD-1 or to overcome suppressive mechanisms employed by the tumor microenvironment. Using both in vivo and in vitro assays, we have identified both a novel target that provides an enhancement to CD8 T-cell effector function when in combination with PD-1 checkpoint blockade, and CD8 T-cell-intrinsic pathways that are modulated by the presence of suppressive cells associated with the tumor microenvironment.

Citation Format: Adam N.R Cartwright, Peng Jiang, Assieh Saadatpour, Guo-Cheng Yuan, Shirley X. Liu, Kai W. Wucherpfennig. Overcoming CD8 T-cell suppression in the tumor microenvironment [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 A176.