Initiation and Evolution of the Ovarian Cancer Microenvironment

摘要 尽管它的侵略性和突变的新表位的稀缺性，多线证据支持， 卵巢癌确实是免疫原性的3 -11。了解这些反应的性质及其 特别是卵巢癌的动态将是这次竞争性更新的重点。关键实验结果 支持这一提议的是：1）在TCGA数据集中鉴定出许多卵巢癌， T细胞介导的细胞溶解活性和零错义突变或移码的强标志物; 2）事实 所有这些没有突变的新抗原的免疫原性肿瘤都显示内源性 逆转录病毒（ERV）;和3）鉴定结合外显子的一类新的嵌合新抗原 由重新激活的内源性逆转录病毒加上来自附近蛋白质编码基因的外显子编码。基于 根据我们的这些和其他发现，我们的中心假设是卵巢癌的免疫原性部分是由 通过内源性逆转录病毒的再活化，导致嵌合抗原的产生， 卵巢恶性肿瘤的免疫原性随着疾病的进展而增强， 免疫抑制环境。 在目标1中，我们将确定逆转录病毒驱动的嵌合抗原在免疫保护中的作用， 卵巢癌这些结果将证实一类新的肿瘤特异性抗原的存在， 来自ERV的重新激活，预期ERV将以有限的免疫原性驱动肿瘤的免疫原性。 突变的新抗原库。 在目标2中，我们将定义重新激活的内源性逆转录病毒在抗肿瘤进化中的作用。 免疫力支持我们的初步结果，这些数据有望证实一个新的框架， 了解对卵巢癌的保护性免疫的动力学和驱动因素，基于延迟但 进行性免疫原性，很大程度上独立于突变的新抗原。 在目标3中，我们将阐明导致人类卵巢癌中ERVs重新激活的机制 以及相应的免疫原性的内在驱动因素。 我们的工作将在该领域产生深远的影响，通过充实一个新的“抑制累积” 免疫原性”框架来解释肿瘤中抗肿瘤免疫的动力学， 突变的新抗原的突变，但高表达的逆转录病毒嵌合抗原，这将补充 理解免疫编辑假说为致癌物诱导的肿瘤提供了条件。

ABSTRACT Despite its aggressiveness and scarcity of mutated neo-epitopes, multiple lines of evidence support that ovarian carcinomas are truly immunogenic3-11. Understanding the nature of those responses and their dynamics specifically in ovarian cancer will be the focus of this competitive renewal. Key experimental findings supporting this proposal have been: 1) the identification of many ovarian cancers in TCGA datasets exhibiting strong markers of T cell-mediated cytolytic activity and ZERO missense mutations or frameshifts; 2) the fact that all of these immunogenic tumors without mutated neo-antigens show re-activation of endogenous retroviruses (ERVs); and 3) the identification of a new class of chimeric neo-antigens combining exons encoded by re-activated endogenous retroviruses plus exons from nearby protein-coding genes. Based on these and other of our findings, our central hypothesis is that immunogenicity in ovarian cancer is in part driven by the re-activation of endogenous retroviruses, resulting in the generation of chimeric antigens, so that ovarian malignancies become more - not less - immunogenic as the disease progresses in an immunosuppressive environment. In Aim 1, we will determine the role of retrovirally-driven chimeric antigens in immune protection against ovarian cancer. These results will validate the existence of a new class of tumor-specific antigens resulting from the re-activation of ERVs, which are expected to drive the immunogenicity of tumors with a limited repertoire of mutated neo-antigens. In Aim 2, we will define the role of re-activated endogenous retroviruses in the evolution of anti-tumor immunity. Supporting our preliminary results, these data are expected to substantiate a new framework to understand the dynamics and drivers of protective immunity against ovarian cancer, based on delayed but progressive immunogenicity, largely independent of mutated neo-antigens. In Aim 3, we will elucidate the mechanisms leading to the re-activation of ERVs in human ovarian cancer and, correspondingly, the intrinsic drivers of the immunogenicity. Our work will exert a profound effect in the field by substantiating a novel “suppressed cumulative immunogenicity” framework to explain the dynamics of anti-tumor immunity in tumors with a limited number of mutated of mutated neo-antigens but high expression of retroviral chimeric antigens, which will complement the understanding that the immunoediting hypothesis has provided for carcinogen-induced tumors.