Abstract B083: Defective transcription elongation in a subset of cancers confers immunotherapy resistance

Abstract

Abstract Immunogenicity of most cancer types is a result of either neoantigenic mutational load, which stokes up an adaptive immune response, or due to oncogenic stress pathways, which elicit an innate antitumor response. There have been exponential gains made in recent times using numerous strategies to reactivate the host antitumor immunity including the development of immune checkpoint inhibitors. Nonetheless, the promise of a cure and durable response in select patients does not refute the low response rates in advanced cases, most of which also relapse. These observations shore up the possibility of other mechanisms beyond the inactivation of local lymphocyte infiltrates that might also play in tumor cell evasion of antitumor immune response. Through comprehensive computational and follow-up experimental validations, we have found that a subset of cancers (~15-20% of all cancers) are characterized by severe defects in almost the entire epigenetic and transcriptional apparatus. These defects result in genome-wide deregulation of histone modifications, mRNA transcription elongation, and mRNA processing and nuclear export, especially in the long genes which we term as Transcriptional Elongation Deficient: TEdef. As such, cancer cells with TEdef suppressed the expression of the pathways enriched for long genes, such as proinflammatory signaling pathways (FasL response, TNF/NF-kB signaling, interferon signaling) at both mRNA and protein levels, and had diminished response to interferon and TNF stimuli. Remarkably, in renal cell carcinoma and metastatic melanoma patients in four cohorts, the TEdef phenotype significantly correlated with poor response and unfavorable outcome to immunotherapy, but not to chemo- or targeted therapy. Importantly, forced induction of TEdef in tumor cells impaired the expression of, and signaling through, the proinflammatory pathways, and imposed a resistance to the innate and adaptive antitumor immune responses and to immune checkpoint inhibitor therapy in vivo. Tumor lymphocyte infiltration (TIL) and somatic neoepitope load (SNL) are some of the best markers of immunotherapy response in the clinic. However, TEdef tumors were characterized by a higher rate of immune cell infiltration, but paradoxically, less immune-mediated local tumor cell lysis, further supporting the notion that TEdef is a tumor cell-autonomous mechanism of immune resistance. As such, combining TIL or SNL with TEdef had superior power in predicting the progression-free and overall survival of melanoma patients treated with the anti-CTLA4 and anti-PD-1 therapy. Overall, TEdef is a novel epigenetic mechanism of resistance to antitumor immune attack, which warrants its assessment in cancer patients undergoing immunotherapy. Citation Format: Vishnu Modur. Defective transcription elongation in a subset of cancers confers immunotherapy resistance [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B083.