32nd Annual Meeting and Pre-Conference Programs of the Society for Immunotherapy of Cancer (SITC 2017): Part One
Authors: Vinod Balachandran, Marta Luksza, Julia Zhao, Vladimir Makarov, John Moral, Romain Remark, Brian Herbst, Gokce Askan, Umeshkumar Bhanot, Yasin Senbabaoglu, Danny Wells, Ian Charles, Olivera Grbovic-Huezo, Marc Attiyeh, Benjamin Medina, Jennifer Zhang, Jennifer Loo, Joseph Saglimbeni, Mohsen Abu-Akeel, Roberta Zappasodi, Nadeem Riaz, Martin Smoragiewicz, Olca Basturk, Mithat Gönen, Arnold Levine, Peter Allen, Douglas Fearon, Miriam Merad, Sacha Gnjatic, Christine Iacobuzio-Donahue, Jedd Wolchok, Ronald Dematteo, Benjamin Greenbaum, Taha Merghoub, Steven Leach, Priyanka Subrahmanyam, Zhiwan Dong, Daniel Gusenleitner, Anita Giobbie-Hurder, Mariano Severgnini, Jun Zhou, Michael Manos, Holden Maecker, F Hodi, Nathalie Harder, Harald Hessel, Maria Athelogou, Alexander Buchner, Christian Stief, Thomas Kirchner, Günter Schmidt, Ralf Huss, Andrew Hotson, John Powderly, Leisha Emens, Patrick Forde, Matthew Hellman, Lawrence Fong, Ben Markman, Brett Hughes, Jonathan Goldman, Mario Sznol, Daruka Mahadevan, Shivaani Kummar, Joshua Brody, Philip Bonomi, Jason Luke, Matthew Riese, Taofeek Owonikoko, Sherene Loi, Amy Wiese, Robert Doebele, James Lee, Chunyan Gu, Stephen Willingham, Ginna Laport, Richard Miller, Ian Mccaffery, Nina Bhardwaj, Philip Friedlander, Anna Pavlick, Marc Ernstoff, Brian Gastman, Brent Hanks, Mark Albertini, Michael Yellin, Tibor Keler, Thomas Davis, Laura Vitale, Ana Blazquez, Chihiro Morishima, Patrick Danaher, Sarah Warren, Bob Salim, Bruce Hess, Leonard D'amico, Lisa Lundgren, Nora Disis, Martin Cheever, Steven Fling
Journal: Journal for ImmunoTherapy of Cancer (2017)

BackgroundPancreatic adenocarcinoma (PDAC) is a lethal cancer with <7% of patients surviving past 5 years.T cell immunity has been linked to the exceptional outcome of the rare long-term survivors but the antigens are unknown.Methods To identify T cell antigens in long-term PDAC survivors, we assembled the largest cohorts of stage-matched short [n=68, median overall survival (OS) 0.8y] and long-term PDAC survivors (n=82, median OS 6y).To enable antigen discovery, we performed a combined analysis of whole exome sequencing, neoantigen prediction, T cell receptor (TCR) Vβ-chain sequencing, 9-color multiplexed immunohis-tochemistry, and tumor transcriptomic profiling.To assess differential neoantigen immunogenicity, we performed neoantigen fitness modeling integrating clonal genealogy, epitope homology, and T cell receptor affinity.To examine in vivo T cell-neoantigen reactivity, we used functional assays in a subset of very long-term PDAC survivors (n=7, median OS 10.5 years). ResultsWe found that tumors of long-term survivors displayed 12-fold greater cytolytic CD3 + CD8 + Granzyme-B + cells, with >94% of intratumoral T cell clones unique to tumors and not shared with adjacent normal pancreatic tissue, suggesting intratumoral antigen recognition.Tumors of long-term survivors exhibited greater TCR repertoire diversity compared to tumors of short-term survivors, implying differential antigenic targets.In examining neoantigens as potential T cell targets, we found that patients with both the highest predicted neoantigen number and the greatest CD3 + CD8 + infiltrates together but not either parameter alone, exhibited the longest survival (median OS not reached vs. 0.8y, P=0.004).In investigating possible unique neoantigen qualities in long-term survivors, a neoantigen quality model conferring greater immunogenicity to dominant neoantigens with homology to microbial epitopes identified longterm survivors independent of confounding variables and chemotherapy (Neoantigen Quality Hi vs. Low -median OS 8.6y vs. 0.8y; P=0.002) whereas a model ascribing greater immunogenicity to increasing neoantigen number did not (Neoantigen Quantity Hi vs. Lowmedian OS 0.8y vs. 1y; P=0.3) (Fig. 1).Similarly, neoantigen quality, but not quantity, was independently prognostic of survival in a larger, independent cohort unselected by survival (n =166; Neoantigen Quality Hi vs. Low -median OS 30m vs. 14m; P<0.0001) (Fig. 1).Finally, we detected lasting circulating T cell reactivity to both high quality neoantigens and cross-reactive antigens in PDAC survivors, including identical intratumoral clones with specificity to both (n=5 of 7 patients tested). ConclusionsOur results identify neoantigens with unique qualities as T cell targets in PDAC.More broadly, we identify neoantigen quality as a biomarker for immunogenic tumors that may facilitate rational application of immunotherapies.