Abstract 5390: microRNA signature of T cell exhaustion

Background: T cell exhaustion is driven by persistence of antigen and inflammation, common features of cancer. The success of a checkpoint inhibitor blockade may depend upon reactivation of pre-existing tumor-specific CD8+ T cells in the tumor microenvironment. Using an in vitro model and tumor infiltrating lymphocytes (TILs) isolated from multiple tumors, we explored microRNAs (miRNA, miR) involved in T cell dysfunction in order to identify pathways that may be important for altering this phenotype following immunotherapy. Methods: We used an established in vitro model of T cell exhaustion: healthy donor CD8+ T cells were stimulated with anti-CD3/CD28 for six days. We used RNASeq and quantitative PCR to evaluate genomic (mRNA and microRNA (miR)) changes associated with T cell function and paired differentially expressed microRNAs with predicted target genes. Exhaustion of CD8+ TILs isolated from melanoma (n = 2), NSCLC (n = 3), renal (n = 3), bladder (n = 10), and colorectal tumors (n = 2) was measured by flow cytometry analysis of PD-1/TIM-3. miRNA and mRNA relationships identified by the in vitro model were evaluated in a subset of TILs from NSCLC, renal, and bladder tumors (n = 6). Results: Results showed expected phenotypic and functional changes across 6 donors stimulated chronically with anti-CD3/CD28: 2-4-fold increased PD-1 and TIM-3 surface expression with a 3-5-fold loss of intracellular IFNg production (p 2-fold in tumors with high miR signature, while in renal cancer, B cell and CD40 pathway signatures were enriched. In melanoma, high miR signature showed a trend toward increased myeloid-derived suppressor cell (MDSC) signature expression (>1.5-fold change), while the opposite trend was observed in head and neck cancer. Conclusions: We identified a novel miRNA exhaustion signature associated with immune-related pathways in multiple tumor types. This signature may help generate hypotheses to guide prioritization of specific IO combination treatments. Citation Format: Lydia M. Greenlees, Michael Kuziora, Yinong Sebastian, Todd Creasy, Young S. Lee, Fernanda Pilataxi, Nick Holoweckyj, Li Cheng, Brandon W. Higgs, Koustubh Ranade, Katie Streicher. microRNA signature of T cell exhaustion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5390.