Abstract 81: The association between melanoma liver metastases (mets) and the systemic anti-tumor immune profile
Authors: Conway Jordan W. , Marsh-Wakefield Felix , Nahar Kazi J. , Lo Serigne N. , Vergara Ismael A. , Gide Tuba N. , Attrill Grace H. , Braden Jorja , Carlino Matteo S. , Saw Robyn P. , Thompson John F. , Spillane Andrew J. , Shannon Kerwin F. , Shivalingam Brindha , Menzies Alexander M. , Palendira Umaimainthan , Wilmott James S. , Long Georgina V. , Scolyer Richard A. , Da Silva Ines Pires 
Published: April 2023

Abstract
Purpose Patients with melanoma liver metastases have significantly reduced overall response and survival when treated with immune checkpoint inhibitors (ICI) compared to those without liver metastases. Melanoma liver metastases are less likely to respond to ICI compared to other sites of metastases, and the presence of liver metastases has also been associated with reduced responses to ICI at other metastatic sites. We aimed to profile circulating and tumor immune profiles of melanoma patients with versus without liver metastases to elucidate the factors behind this observation.
Methods Pre-treatment PBMCs from 37 advanced melanoma patients (Cohort A) were profiled using mass cytometry (CyTOF) spanning 46 markers. Expression of specific immune cells were compared between those with (n = 8) vs without (n = 29) liver metastases. In a separate independent cohort of 93 untreated metastatic melanoma patients (Cohort B), FFPE tumour samples comprised of subcutaneous, lymph node (LN) and brain metastases were stained for myeloid and T cell markers using multiplex IHC. Immune cell populations in cohort B tissues were compared between patients with (n=40) vs without (n=53) liver metastases.
Results PBMCs from patients in Cohort A with liver metastases had an increased proportion of a myeloid population characterised as HLA-DR+CD14+CD16- compared to patients without liver metastases (p = 0.035). However, a difference in CD68+CD14+CD16- myeloid cells was not seen in cohort B melanoma tissues (subcut, LN, brain metastases) between patients with vs without liver metastases. In subcutaneous tissues, there was a significantly reduced density of T cells in patients with liver metastases (median = 59 cells/mm2) compared to those without (median = 217 cells/mm2; p = 0.037). This trend was also observed in LN and brain metastases but did not reach significance. In brain metastases, a higher proportion of FoxP3+ T cells was observed in patients with liver metastases (p = 0.003). An increase in this population was also observed in the LN and subcutaneous metastases in the presence (vs absence) of liver metastases, however this did not reach significance. LN metastases also showed a reduced proportion of both TIM3+ (p = 0.049) and CD103+ (p = 0.048) T cells in patients with liver metastases (vs absence), and a similar trend was observed in subcutaneous metastases. In contrast, brain metastases showed the opposite trend as well as higher proportion of PD1+ T cells in patients with liver metastases vs those without (p = 0.033).
Conclusion These data provide insights into the differences in the anti-tumor immune profiles of patients with versus without liver metastases; the presence of liver metastases may have a specific impact at different metastatic sites. This highlights the need for further validation and investigation into the mechanism by which the presence of liver metastases may exert this effect.
Citation Format: Jordan W. Conway, Felix Marsh-Wakefield, Kazi J. Nahar, Serigne N. Lo, Ismael A. Vergara, Tuba N. Gide, Grace H. Attrill, Jorja Braden, Matteo S. Carlino, Robyn P. Saw, John F. Thompson, Andrew J. Spillane, Kerwin F. Shannon, Brindha Shivalingam, Alexander M. Menzies, Umaimainthan Palendira, James S. Wilmott, Georgina V. Long, Richard A. Scolyer, Ines Pires Da Silva. The association between melanoma liver metastases (mets) and the systemic anti-tumor immune profile [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 81.