Abstract PR03: Combinatorial blockade of PD-1, CTLA-4, and LAG-3 pathways inhibits murine ovarian tumor growth.

Abstract

Abstract We have previously shown that tumor-associated or infiltrating T cells (TALs or TILs) often co-express immune inhibitory receptors lymphocyte activation gene-3 (LAG-3) and programmed cell death 1 (PD-1) in human and murine ovarian tumor microenvironment (TME). Dual antibody blockade or genetic knockout of LAG3 and PD1 significantly enhanced T effector function and delayed ovarian tumor growth. The relative contribution of other immune inhibitory receptors to immune suppression in the ovarian TME, and whether they co-regulate each other are currently unknown. To address this, we analyzed the expression of multiple immune checkpoint proteins and their cognate ligands in ovarian tumor-bearing wild-type (WT), LAG3KO and PD1KO mice. We found that PD-1, cytotoxic T lymphocyte antigen 4 (CTLA-4), LAG-3, T-cell immunoglobulin domain and mucin domain 3 (TIM-3) and CD160 were elevated in TILs from the WT mice. Interestingly, compared with TILs of WT mice, the levels of LAG-3, TIM-3, and CTLA-4 were further significantly elevated in TILs from the tumor-bearing PD1KO mice; while the levels of PD-1, CTLA-4, and CD160 were further increased in the tumor-bearing LAG3KO mice. These results suggest that PD-1 and LAG-3 regulate the expression of multiple inhibitory receptors in the ovarian TME. Furthermore, combinatorial blockade with anti-LAG3 and anti-CTLA4 antibodies in the tumor-bearing PD1KO mice resulted in 30% tumor-rejection as compared to 10% by anti-CTLA4 alone or only delayed tumor growth by anti-LAG3. These data provide a strong basis for rational clinical testing of combinatorial blockade of the PD-1, LAG-3 and CTLA-4 immune inhibitory pathways for ovarian cancer immunotherapy. This abstract is also presented as Poster A51. Citation Format: Ruea-Yea Huang, AJ McGray, Kunle Odunsi. Combinatorial blockade of PD-1, CTLA-4, and LAG-3 pathways inhibits murine ovarian tumor growth. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr PR03.