Regulation of human endogenous retroviruses in the context of cancer immunotherapy

San Raffaele Hospital, Milano

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Abstract

ABSTRACT Immunotherapies are the most rapidly growing drug class and have a major impact in oncology and on human health. Nevertheless, only a minority of patients display long-term beneficial response to cancer immunotherapies and checkpoint inhibitors. The effectiveness of immunomodulatory strategies strongly depends on the presence of a pre-existing intratumoral immune response. Indeed, patient stratification according to their immune infiltration can accurately predict cancer survival upon immunotherapy. Understanding the mechanisms stimulating intratumoral T cell infiltration could allow the development of approaches to transform ?cold? onto ?hot? tumors and increase the efficacy of immunotherapies. A large portion of the tumor epitopes are encoded by repetitive sequences, including endogenous retroviruses (ERVs). Accordingly, high ERV expression positively correlates with intratumoral T cell infiltration, overall survival and progression-free survival upon immunotherapy. Nevertheless, little is known regarding direct regulators of ERV gene expression in cancer. Our preliminary data promote double homeobox 4 (DUX4) as an activator of ERV transcription in cancer. DUX4 is physiologically expressed in a narrow window of early embryonic development in which it directly activates hundreds of protein-coding genes and retroviral elements (including ERVs) that define the cleavage-specific transcriptional programs. Normally silent in most adult tissues, DUX4 is re-expressed in a wide range of cancer types. We found that DUX4 expression is significantly and positively correlated with that of immunogenic ERVs and the presence of an intratumoral immune response. Moreover, we discovered that treatments promoting tumor antigen presentation, anti-tumor immunity and working synergistically with immunotherapies induce DUX4 expression and its immunogenic ERV targets. We now propose to address fundamental questions to dissect the molecular mechanism underlying the transcriptional regulation ERV expression by DUX4 and test its relevance for cancer immunotherapy. Which are the ERVs directly controlled by DUX4 in cancer cells? Is DUX4 required for ERV activation by epigenetic drugs? Does DUX4 promote anti-tumor immunity? We will address these questions by using a combination of in vivo and in vitro experiments and cutting edge technologies with the long-term aim to design better drugs and target them to the tumor microenvironment. A better characterization of ERV transcriptional regulation is urgent and has clear translational application, as they are one of the main sources of targetable tumor-specific antigens and immunotherapy response in cancer.