Relationship between liver metastases and PD-1 blockade in melanoma.

Abstract

3072 Background: WhilePD-1 blockade is effective in melanoma, durable responses remain elusive. We have previously reported that liver metastasis is associated with reduced response rates and that the fraction of CTLA4 hi/PD-1 hi CD8+ cells (“activated-exhausted” or T-ex cells) within the TIL is predictive of response to PD-1 blockade. Here, we explore the biology behind liver metastasis in human melanoma and in animal models. Methods: Patients with metastatic melanoma with or without liver metastasis were biopsied pre- PD-1 treatment and immune infiltrates were analyzed by FACS. The CD8 fraction was gated on CTLA4 and PD-1. C57BL/6 mice were implanted with a “primary” subcutaneous tumor and a “metastatic” tumor in the liver or the lungs (control), and given systemic PD-1 blockade therapy. Results: Patients with melanoma and liver metastasis (n = 25) had 15.2% T-ex cells while those without liver metastasis (n = 76) had 26.5 % T-ex cells, p = 0.0092. A T-ex fraction < 20% was significantly associated with lack of PD-1 response, p < 0.005. In C57BL/6 mice implanted with a B16 tumor (subQ & liver) treated with PD-1 antibody, 0/35 mice achieved subQ tumor rejection while in the SubQ only mice 9/30 mice (30%) rejected their tumors. The mean tumor size of mice with Sub Q+liver metastasis was 139.2 mm2 vs subQ only mice 23.4 mm2 at d 14, p = 0.002. Mice with liver metastasis showed a T-ex fraction 31.9% vs 67.3%without liver met, p = 0.0003. In contrast, in mice made lung metastatic, the subQ tumor rejection rate was 7/20 (35%), with T-ex infiltrate at 57.9%. The implantation of liver metastases from an unrelated MC38 tumor does not protect the subQ tumor from immune rejection. Conclusions: The presence of liver metastases is associated with reduced response to PD-1 blockade and reduced T-ex infiltrate in patients with stage IV melanoma. Mechanistic studies using a mouse model of syngeneic organ site specific metastasis confirms that the liver metastasis results in reduced antigen specific T cell at distant sites, resulting in reduced response. Site of metastasis may determine immune responsiveness in both mouse models and in humans with melanoma.