Abstract B33: Loss of transcriptional fidelity in cancers confers immunotherapy resistance

Most cancers are immunogenic, either due to neo-antigenic mutational load that makes them susceptible to rejection by the adaptive immune system, or due to oncogenic stress pathways that makes them vulnerable to innate anti-tumor responses. The therapeutic strategies to reactivate the host anti-tumor immunity have a great promise for cancer therapy. However, despite the unprecedented promise of a cure and durable disease management in select patients, the response rates are still low in advanced cases, most of which also relapse. These findings reflect the multitude of mechanisms of tumor cell evasion of anti-tumor immunity, and that mechanisms beyond inactivation of local lymphocyte infiltrates might also play a role. Through comprehensive computational and follow-up experimental validations, we have found that a subset of cancers (~15-20% of all cancers) is characterized by severe defects in almost the entire epigenetic and transcriptional apparatus, resulting in genome-wide deregulation of histone modifications, mRNA transcription elongation, splicing and processing (Loss of Transcriptional Fidelity: LTF). LTF impaired the transcription of long genes in the genome at both mRNA and protein levels; and the pathways that are primarily regulated by long genes, such as immune-related (FasL response, TNF/NF-kB signaling, interferon signaling), MAP kinase and tyrosine kinase signaling pathways, were significantly suppressed in LTF+ (i.e. those with LTF) tumors. We validated the LTF phenotype and associated epigenetic and transcriptional defects in some cancer cell lines, and showed that severe loss of transcriptional fidelity can confer resistance to pro-inflammatory anti-tumor mechanisms in vitro, and suppress immune-mediated tumor rejection in vivo. As such, we found that LTF predicted poor response to immunotherapeutic, but not to chemo- or targeted therapy, agents in the clinic, including immune checkpoint inhibitors, in 3 different cohorts. Therefore, LTF is a previously unknown global phenotype in cancer cells that confers cell-autonomous resistance to anti-tumor immune attacks. Tumor lymphocyte infiltration is one of the best markers of immunotherapy response in the clinic. However, LTF+ 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 LTF is a tumor cell-autonomous mechanism of immune resistance. As such, combining tumor lymphocyte infiltration with LTF had superior power in predicting the progression-free and overall survival of melanoma patients treated with the anti-CTLA4 antibody ipilimumab. This study uncovers a major phenotype in cancers that dictates global transcriptional and signaling state in the cell, and response to immunotherapeutic agents in the clinic. Further, this study warrants assessment of markers of LTF in immunotherapy-candidate patients, especially given that LTF+ kidney cancer patients had significantly better response to targeted therapy agents. Citation Format: Navneet Singh, Vishnu Modur, Vakul Mohanty, Kwangmin Choi, Edith M. Janssen, Lisa Privette-Vinnedge, Gang Huang, Kakajan Komurov. Loss of transcriptional fidelity in cancers confers immunotherapy resistance. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B33.