Abstract PR03: Determine a transcriptional mechanism novel to tumor infiltrating T cell dysfunction

Detection of functional tumor infiltrating T cells (TIL) positively correlates with improved prognosis and overall survival cancer patient. However, TIL are subjected to immune evasion and tolerance mechanisms that suppress defense against tumor growth. Therefore, TIL usually have a dysfunctional phenotype in solid tumor microenvironments. Such dysfunction includes decreased proliferation and progression through the cell cycle. Using the CT26 colorectal cancer model in mice, we readily detect T cells specific for the immunodominant tumor-associated antigen, AH1 (gp70 423-431 ). To determine potential therapeutic targets, we compared gene expression profiles of tumor-specific T cells from the tumor and periphery. The results of this comparison highlight many known, hypothesized, and potential new mechanisms underlying TIL dysfunction. Gene set enrichment analysis of genes differentially regulated by TIL have significant overlap with those of exhausted LCMV-specific T cells published by Wherry in 2007. As expected, differentially expressed genes in TIL were also highly associated by pathway analysis with inhibition of T cell progression through cell cycle and decreased proliferation (Ingenuity). We have verified our microarray data by protein and functional analyses. TIL coexpress higher protein levels of multiple inhibitory receptors, produce less IFNγ, and progress less through the cell cycle in response to peptide stimulation. Studies by others suggest that E2F1 and E2F2 are involved in regulation of T cell progression through the cell cycle and proliferation. The following statistical analyses suggested members of the transcription factor family E2F are regulators of TIL dysfunction: 1) The top five transcription factor motifs found to be enriched in promoter regions of genes up-regulated by TIL are all variants for E2F1 (p This abstract is also presented as Poster A57. Citation Format: Katherine A. Waugh, Sonia Leach, Jill E. Slansky. Determine a transcriptional mechanism novel to tumor infiltrating T cell dysfunction. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr PR03.