Abstract LB-301: Inhibition of the co-inhibitory receptor KLRG1 reduces murine 4T1 breast cancer metastasis and MC38 colon cancer primary tumor growth and mortality

Abstract

Abstract Introduction Targeting of lymphocyte co-inhibitory receptors, such as CTLA-4, PD-1, Lag-3, and Tim-3, has gained intense interest for treatment of cancer. KLRG1 is also a lymphocyte co-inhibitory receptor, expressed predominantly on effector memory CD8+ T cells and NK cells, whose ligands E- and N-cadherin are differentially expressed during epithelial-mesenchymal transition. Targeting of KLRG1 in murine cancer models has not previously been published. Methods We constructed an anti-mouse KLRG1 antibody that neutralized the interaction of KLRG1 with its ligands. Anti-KLRG1 antibody was administered as a monotherapy in a murine metastatic tumor model (4T1 murine breast cancer) and as combination therapy with anti-PD-1 (clone RMP1-14) in a murine primary tumor growth model (MC38 murine colon cancer). Results In the 4T1 murine breast cancer model, anti-KLRG1 antibody reduced lung metastases compared to control antibody as measured by mean lung weights (0.28 g vs. 0.47 g; p=0.04) and nodule count (10.7 vs. 30.1; p=0.002). In the MC38 model, primary tumor growth was inhibited by anti-KLRG1 + anti-PD-1 antibody greater than anti-KLRG1 antibody or anti-PD-1 antibody or control antibody (day 13 tumor volume 582 vs. 1259 vs. 1279 vs. 1461 mm3, respectively). Combination therapy anti-KLRG1 + anti-PD-1 produced synergistic benefit significantly greater than that of anti-PD-1 alone for tumor volume (p=0.01) and survival (p=0.02; day 18 survival 60% of mice alive treated with combination therapy compared to 0% alive treated with anti-PD-1 alone). Ex vivo KLRG1 blockade with anti-human KLRG1 antibodies resulted in human CD8+ T cell proliferation and proinflammatory cytokine secretion. Conclusions Anti-KLRG1 neutralizing antibody demonstrates efficacy in inhibiting metastases in the murine 4T1 breast cancer model and reducing primary tumor volume and improving survival as synergistic combination therapy with anti-PD-1 in the murine MC38 colon cancer model. Anti-KLRG1 blockade with anti-human KLRG1 antibodies results in activation of CD8+ T cells. These data suggest that anti-KLRG1 treatment is a promising new approach for cancer immunotherapy. Citation Format: Steven A. Greenberg, Stefano V. Gulla, Evan Thompson. Inhibition of the co-inhibitory receptor KLRG1 reduces murine 4T1 breast cancer metastasis and MC38 colon cancer primary tumor growth and mortality [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 LB-301.