Abstract 975: Liver metastases (mets) induce systemic immunosuppression and immunotherapy resistance in metastatic melanoma

Melanoma patients (pts) with liver mets have a lower response rate (RR), and shorter progression-free (PFS) and overall survival (OS) compared to pts without liver mets when treated with anti-PD-1 (PD1) therapy. The liver microenvironment (ME) induces T-cell tolerance through the interaction of T cells with liver sinusoidal endothelial cells. To explore this further we compared clinicopathological features, circulating cytokines and tumor gene expression (GE) profiles of pts with and without liver mets treated with PD1 combined with ipilimumab (PD1+IPI), and treated with BRAF targeted therapy (TT). Demographics, disease characteristics and outcome data were collected from 140 pts treated with PD1+IPI and from 76 pts treated with BRAF+/-MEKi. Tumor-infiltrating lymphocytes (TILs) immunoreactivity score (TILs density x % of tumor with TILS), % of tumor content, necrosis and fibrosis were assessed by immunohistochemistry in liver and lung samples. Pre-treatment circulating cytokines and tumor GE data (RNA seq) were compared between pts with and without liver mets. In pts treated with IPI+PD1, liver mets had the lowest tumor regression (med -7%) compared to all other sites of disease (med -66%), while in TT-treated pts the response was similar across all sites of disease. Pts with liver mets (n=39) had lower RR (44% v 75%), and shorter median PFS and OS (p Pts with liver mets display distinct clinicopathological features, distinct circulating cytokines and melanoma GE profiles, and are less responsive to PD1+IPI compared to pts without liver mets. The levels of Eotaxin-2, IP-10 and IL-8 are higher in melanoma pts with liver mets compared to pts without liver mets, similar to what is seen in pts with colon cancer liver mets. Liver mets’ ME may hold unique immunosuppressive mechanisms that are amenable to therapeutic targeting. Citation Format: Ines Silva, Annie Tasker, Camelia Quek, Robert Rawson, Su Yin Lim, Kevin Wang, Jordan Conway, Rebecca Velickovic, Tasnia Ahmed, Serigne Lo, Jean Yang, Helen Rizos, James S. Wilmott, Richard A. Scolyer, Alexander M. Menzies, Georgina V. Long. Liver metastases (mets) induce systemic immunosuppression and immunotherapy resistance in metastatic melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 975.