Abstract 975: Liver metastases (mets) induce systemic immunosuppression and immunotherapy resistance in metastatic melanoma
Authors: Silva Ines , Tasker Annie , Quek Camelia , Rawson Robert , Lim Su Yin , Wang Kevin , Conway Jordan , Velickovic Rebecca , Ahmed Tasnia , Lo Serigne , Yang Jean , Rizos Helen , Wilmott James S. , Scolyer Richard A. , Menzies Alexander M. , Long Georgina V. 
Published: August 2019

Abstract
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&lt;0.05) when treated with IPI+PD1 than those without liver mets (n=101). In contrast, in pts treated with TT, RR, PFS and OS were similar between pts with (n=19) vs without (n=57) liver mets. Pts with liver mets had less response in adrenal and LN mets when treated with IPI+PD1 compared to pts without liver mets, but not with TT. In a multivariate analysis performed on the PD1+IPI cohort and validated in the TT group, presence of bone (OR 4.6 p=0.004) and spleen mets (OR 13.5 p=0.01) were associated with the presence of liver mets. Compared to lung mets (n=22), liver mets ME (n=22) had a lower TILs immunoreactivity score (med 30 vs 80, p=0.05), while there was no difference in the % of tumor content, fibrosis or necrosis. The expression of 65 cytokines was measured in plasma of treatment-naive pts; pts with liver mets (n=37) had higher levels of Eotaxin 2 (p=0.01), IP-10 (p=0.02) & IL-8 (p=0.03) compared to pts without liver mets (n=99). GE analysis of melanoma samples showed higher expression of MMP-8 and HIF1a in pts with (n=58) vs without (n=28) liver mets, validated in an independent cohort (n=58).
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.