Abstract PR-003: High quality neoantigens are immunoedited in long-term pancreatic cancer survivors
Authors: Rojas Luis A. , Łuksza Marta , Sethna Zachary M. , Soares Kevin , Leung Joanne , Lihm Jayon , Hoyos David , Dobrin Anton , Kappagantula Rajya , Makohon-Moore Alvin , Johns Amber , Gill Anthony , Amisaki Masataka , Guasp Pablo , Zebboudj Abderezak , Yu Rebecca , Chandra Adrienne Kaya , Odgerel Zagaa , Sadelain Michel , Patterson Erin , Iacobuzio-Donahue Christine , Greenbaum Benjamin D. , Balachandran Vinod P. 
Published: November 2021

Abstract
Cancer immunoediting is a hallmark of cancer that predicts T cells recognize and kill tumor cells expressing immunogenic mutations (neoantigens), to induce less immunogenic clones to outgrow in tumors. Although established through longitudinal studies of how tumors evolve in immune-proficient and -deficient mice, whether the human immune system naturally targets neoantigens to edit tumors remains unclear. Here, we investigate how 70 human pancreatic ductal adenocarcinomas (PDACs) – a poorly immunogenic cancer with few neoantigens and thus largely presumed to not be subject to immunoediting – evolved over 10 years. We use longitudinal tumor sampling to compare how primary tumors evolve to recurrence in rare long-term PDAC survivors previously shown to have more immunogenic tumors (n = 9 patients, n = 9 primary and 22 recurrent tumors, median survival 5.4 years), to short-term survivors with less immunogenic primary tumors (n = 6 patients, n = 6 primary and 33 recurrent tumors, median survival 1.8 years). Compared to short-term survivors, we observe that long-term survivors evolve fewer recurrent tumors with longer latency, and distinct tissue tropism. To evaluate if differential immune pressures could explain these differences, we perform whole exome sequencing to bioinformatically predict tumor clonal structures and neoantigens. We discover that despite longer times to evolve, long-term survivors evolve genetically less heterogeneous tumors with fewer clones, fewer nonsynonymous mutations, and fewer neoantigens. To identify the edited neoantigens, we sought to improve upon and apply our previously defined quality model that quantifies the immunogenic features of a neoantigen. With our quality model, we now infer a neoantigen is immunogenic (“high quality”) by two parameters – if the immune system can recognize a neoantigen as “non-self” by its similarity to known immunogenic antigens, and discriminate it from “self” by estimating if a neoantigen has sufficient antigenic distance from its wild-type peptide to differentially bind the MHC or activate a T cell. We integrate these features to estimate neoantigen quality in primary and recurrent tumors of long- and short-term survivors. With the quality model, we observe that neoantigens with greater antigenic distance (“less self”) are more depleted in primary and recurrent tumors of long- compared to short-term survivors. Furthermore, we find that long-term survivors evolve markedly fewer new neoantigens of strikingly lower quality, to indicate clones with high quality (more immunogenic) neoantigens are immunoedited. Thus, we submit longitudinal evidence that the human immune system naturally edits neoantigens in PDAC. Furthermore, we present a model that describes how cancer neoantigens evolve under immune pressure over time, with implications for cancer biology and therapy. More broadly, our results argue that immunoediting is a fundamental cancer suppressive mechanism that can be quantified to predict tumor evolution.
Citation Format: Luis A. Rojas, Marta Łuksza, Zachary M. Sethna, Kevin Soares, Joanne Leung, Jayon Lihm, David Hoyos, Anton Dobrin, Rajya Kappagantula, Alvin Makohon-Moore, Amber Johns, Anthony Gill, Masataka Amisaki, Pablo Guasp, Abderezak Zebboudj, Rebecca Yu, Adrienne Kaya Chandra, Zagaa Odgerel, Michel Sadelain, Erin Patterson, Christine Iacobuzio-Donahue, Benjamin D. Greenbaum, Vinod P. Balachandran. High quality neoantigens are immunoedited in long-term pancreatic cancer survivors [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PR-003.