Abstract 2357: Identification of microRNAs associated with melanoma immunity and immunotherapy outcome

Abstract

Abstract Introduction:Resistance to immunotherapy is a significant clinical challenge, preventing or limiting response to PD1 checkpoint blockade in approximately 60% of melanoma patients. We sought to identify microRNAs (miRs) that modulate the tumour immune microenvironment and potentially influence outcome to immunotherapy.Methods:To identify miRs associated with immune infiltration and exclusion in melanoma, we first compared miR expression in the human skin cutaneous melanoma (SKCM) dataset from The Cancer Genome Atlas (TCGA) with a selection of immune correlates including histologic assessment of tumour infiltrating lymphocytes (TIL), gene expression-based cytolytic score using Granzyme A and Perforin 1, and transcriptomic estimation of immune cell populations using CIBERSORT. In parallel, we performed miR sequencing of 22 pre-PD-1 inhibitor treatment melanoma tumors to identify differentially-expressed miRs according to PD-1 inhibitor response. We then tested the immune effects of candidate immunomodulatory miRs using microRNA mimics in a panel of human melanoma cell lines, evaluating immunomodulatory cytokine secretion using a bead-based immunoassay (LEGENDplex) and cell surface expression of HLA-A and PD-L1 by flow cytometry.Results:We identified 14 microRNAs associated with immune infiltration or exclusion in the TCGA melanoma dataset. In vitro characterisation of these miRs showed that they regulate secretion of IL-6 and VEGF, and expression of HLA-A in human melanoma cell lines. Furthermore, we identified 25 downregulated and 8 upregulated miRs in responder vs non-responder melanoma lesions (log2 fold change >=1, padj<0.1), including several miRs with high-confidence targets involved in oncogenesis, cancer germline antigens and modification of the extracellular matrix that may impact upon susceptibility to immune attack.Conclusions:This study identified several immunomodulatory miRs associated with immune infiltration in melanoma tumors of TCGA. Several of these candidate immunomodulatory miRs show evidence of activity relevant to the efficacy of PD-1 checkpoint blockade, whilst additional response/resistance-associated miRs were identified. These miRs represent strong candidates for ongoing in vitro and in vivo studies in combination with immunotherapy. Citation Format: Robert A. Szczepaniak Sloane, Miles C. Andrews, Guangchun Han, Lauren Haydu, Elizabeth Burton, Gershenwald E. Jeffrey, Michael A. Davies, Linghua Wang, Scott Woodman, Jennifer Wargo. Identification of microRNAs associated with melanoma immunity and immunotherapy outcome [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 2357.