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Published October 29, 2020 | Supplemental Material
Journal Article Open

Key Parameters of Tumor Epitope Immunogenicity Revealed Through a Consortium Approach Improve Neoantigen Prediction

Wells, Daniel K. ORCID icon
van Buuren, Marit M.
Dang, Kristen K. ORCID icon
Hubbard-Lucey, Vanessa M.
Sheehan, Kathleen C. F. ORCID icon
Campbell, Katie M. ORCID icon
Lamb, Andrew
Ward, Jeffrey P. ORCID icon
Sidney, John
Blazquez, Ana B.
Rech, Andrew J.
Zaretsky, Jesse M. ORCID icon
Comin-Anduix, Begonya
Ng, Alphonsus H. C. ORCID icon
Chour, William ORCID icon
Yu, Thomas V. ORCID icon
Rizvi, Hira
Chen, Jia M.
Manning, Patrice
Steiner, Gabriela M.
Doan, Xengie C.
Merghoub, Taha
Guinney, Justin ORCID icon
Kolom, Adam ORCID icon
Selinsky, Cheryl ORCID icon
Ribas, Antoni
Hellmann, Matthew D. ORCID icon
Hacohen, Nir
Sette, Alessandro
Heath, James R.
Bhardwaj, Nina
Ramsdell, Fred
Schreiber, Robert D.
Schumacher, Ton N. ORCID icon
Kvistborg, Pia ORCID icon
Defranoux, Nadine A. ORCID icon
Khan, Aly A.
Lugade, Amit
Mijalkovic Lazic, Ana M.
Frentzen, Angela A. Elizabeth
Tadmor, Arbel D.
Sasson, Ariella S.
Rao, Arjun A.
Pei, Baikang
Schrörs, Barbara
Berent-Maoz, Beata
Carreno, Beatriz M.
Song, Bin
Peters, Bjoern
Li, Bo
Higgs, Brandon W.
Stevenson, Brian J.
Iseli, Christian
Miller, Christopher A.
Morehouse, Christopher A.
Melief, Cornelis J. M.
Puig-Saus, Cristina
van Beek, Daphne
Balli, David
Gfeller, David
Haussler, David
Jäger, Dirk
Cortes, Eduardo
Esaulova, Ekaterina
Sherafat, Elham
Arcila, Francisco
Bartha, Gabor
Liu, Geng
Coukos, George
Richard, Guilhem
Chang, Han
Si, Han
Zörnig, Inka
Xenarios, Ioannis
Mandoiu, Ion
Kooi, Irsan
Conway, James P.
Kessler, Jan H.
Greenbaum, Jason A.
Perera, Jason F.
Harris, Jason
Hundal, Jasreet
Shelton, Jennifer M.
Wang, Jianmin
Wang, Jiaqian
Greshock, Joel
Blake, Jonathon
Szustakowski, Joseph
Kodysh, Julia
Forman, Juliet
Wei, Lei
Lee, Leo J.
Fanchi, Lorenzo F.
Slagter, Maarten
Lang, Maren
Mueller, Markus
Lower, Martin
Vormehr, Mathias
Artyomov, Maxim N.
Kuziora, Michael
Princiotta, Michael
Bassani-Sternberg, Michal
Macabali, Mignonette
Kojicic, Milica R.
Yang, Naibo
Raicevic, Nevena M. Ilic
Guex, Nicolas
Robine, Nicolas
Halama, Niels
Skundric, Nikola M.
Milicevic, Ognjen S.
Gellert, Pascal
Jongeneel, Patrick
Charoentong, Pornpimol
Srivastava, Pramod K.
Tanden, Prateek
Shah, Priyanka
Hu, Qiang
Gupta, Ravi
Chen, Richard
Petit, Robert
Ziman, Robert
Hilker, Rolf
Shukla, Sachet A.
Al Seesi, Sahar
Boyle, Sean M.
Qiu, Si
Sarkizova, Siranush
Salama, Sofie
Liu, Song
Wu, Song
Sridhar, Sriram
Ketelaars, Steven L. C.
Jhunjhunwala, Suchit
Shcheglova, Tatiana
Schuepbach, Thierry
Creasy, Todd H.
Josipovic, Veliborka
Kovacevic, Vladimir B.
Fu, Weixuan
Krebber, Willem-Jan
Hsu, Yi-Hsiang
Sebastian, Yinong
Kosaloglu-Yalcin, Zeynep
Huang, Zhiqin

Abstract

Many approaches to identify therapeutically relevant neoantigens couple tumor sequencing with bioinformatic algorithms and inferred rules of tumor epitope immunogenicity. However, there are no reference data to compare these approaches, and the parameters governing tumor epitope immunogenicity remain unclear. Here, we assembled a global consortium wherein each participant predicted immunogenic epitopes from shared tumor sequencing data. 608 epitopes were subsequently assessed for T cell binding in patient-matched samples. By integrating peptide features associated with presentation and recognition, we developed a model of tumor epitope immunogenicity that filtered out 98% of non-immunogenic peptides with a precision above 0.70. Pipelines prioritizing model features had superior performance, and pipeline alterations leveraging them improved prediction performance. These findings were validated in an independent cohort of 310 epitopes prioritized from tumor sequencing data and assessed for T cell binding. This data resource enables identification of parameters underlying effective anti-tumor immunity and is available to the research community.

Additional Information

© 2020 Elsevier Inc. Received 30 March 2020, Revised 8 July 2020, Accepted 3 September 2020, Available online 9 October 2020. We thank all the subjects who contributed to this study through donation of tumor and blood samples, as well as the research staff at UCLA and MSKCC for sample collection and processing. We acknowledge Olga Malkova, Diane E. Bender, Likui Yang, and Tammi Vickery for their work on MHC I multimer binding assay and nucleic acid isolation and sequencing; Jeff Bluestone, Jeff Hammerbacher, Ansuman Satpathy, and Robert Vonderheide for helpful and supportive comments; and David Liu and Eliezer van Allen for help in obtaining access to published data. TESLA was conceived collaboratively between the Parker Institute for Cancer Immunotherapy (PICI) and the Cancer Research Institute (CRI), and primary financial support came from PICI, a not-for-profit organization. Additional financial support was provided by NIH (R21 AI34127 to A.S.), an NIH training grant (GM08042 to J.M.Z.), a UCLA Tumor Immunology training grant (NIH T32CA009120), the CRI Irvington Postdoctoral Fellowship Program (to K.M.C.), and the Queen Wilhelmina Cancer Research Award (to T.N.S.). Author Contributions: Conceptualization, V.M.H.-L., A.K., J.G., F.R., and R.D.S.; Methodology, D.K.W., N.A.D., K.K.D., J.G., A.K., N.H., A.S., J.R.H., N.B., F.R., R.D.S., T.N.S., and P.K.; Software, D.K.W., K.K.D., A.L., A.J.R., T.V.Y., X.C.D., and the Tumor Neoantigen Selection Alliance; Validation, M.M.v.B., T.N.S., and P.K.; Formal Analysis: D.K.W. and K.K.D.; Investigation: D.K.W., N.A.D., M.M.v.B., K.K.D., K.C.F.S., K.M.C., J.P.W., J.S., A.B.B., B.C.-A., A.H.C.N., W.C., G.M.S., and the Tumor Neoantigen Selection Alliance; Resources, K.K.D., K.C.F.S., A.L., J.P.W., A.J.R., J.M.Z., B.C-A., T.V.Y., H.R., J.M.C., P.M., the Tumor Neoantigen Selection Alliance, T.M., J.G., C.S., A.R., M.D.H., A.S., J.R.H., N.B., R.D.S., T.N.S., and P.K.S.; Data Curation, D.K.W., N.A.D., M.M.v.B., K.K.D., K.C.F.S., A.L., T.V.Y., H.R., J.M.C., and P.K.; Writing – Original Draft, D.K.W. and N.A.D.; Writing – Review & Editing, D.K.W., N.A.D., M.M.v.B., K.K.D., V.M.H.-L., K.C.F.S., M.D.H., N.H., F.R., R.D.S., T.N.S., and P.K.; Visualization, D.K.W. and N.A.D.; Supervision, N.A.D., D.K.W., M.M.v.B., K.K.D., K.C.F.S.,T.M., J.G., C.S., A.R., M.D.H., N.H., A.S., J.R.H., N.B., F.R., R.D.S., T.N.S., and P.K.; Project Administration, N.A.D., D.K.W., K.K.D., C.S., F.R., and P.K. Declaration of Interests: D.K.W. is a paid scientific advisor and shareholder in Immunai and receives research support from Bristol-Myers Squibb. M.M.v.B. is a stockholder and employee of BioNTech. V.M.H.-L. is an unpaid scientific advisor and holds equity in FX Biopharma. B.C.-A. has a contract grant with Kite Pharma and is a member of the Institutional Biosafety Committee (IBC) at Advarra Inc. N.H. is a stockholder in BioNTech, K.M.C. is a stockholder in Geneoscopy. J.Z. is an equity/stock holder and consultant to PACT Pharma. A.R. has received honoraria from consulting with Amgen, Bristol-Myers Squibb, Chugai, Genentech, Merck, Novartis, and Roche, is or has been a member of the scientific advisory board, and holds stock in Advaxis, Arcus Biosciences, Bioncotech Therapeutics, Compugen, CytomX, Five Prime, FLX-Bio, ImaginAb, Isoplexis, Kite-Gilead, Lutris Pharma, Merus, PACT Pharma, Rgenix, and Tango Therapeutics. M.D.H. receives research support from Bristol-Myers Squibb, has been a compensated consultant for Merck, Bristol-Myers Squibb, AstraZeneca, Genentech/Roche, Nektar, Syndax, Mirati, Shattuck Labs, Immunai, Blueprint Medicines, Achilles, and Arcus, received travel support/honoraria from AstraZeneca, Eli Lilly, and Bristol-Myers Squibb, has options from Shattuck Labs, Immunai, and Arcus, and has a patent filed by his institution related to the use of tumor mutation burden to predict response to immunotherapy (PCT/US2015/062208), which has received licensing fees from PGDx. P.K. is a consultant for Neon Therapeutics and Personalis. J.R.H. is board member and founder of Isoplexis and board member and founder of PACT. F.R. is an advisor/consultant to Equillium Bio, Good Therapeutics, SelectION, Inc., Cascade Drug Development Group, aTyr Pharma, and Lumos Pharma, and is a founder and holds equity in Sonoma Biotherapeutics. R.D.S. is a cofounder, scientific advisory board member, stockholder, and royalty recipient of Jounce Therapeutics and Neon Therapeutics and is a scientific advisory board member for A2 Biotherapeutics, BioLegend, Codiak Biosciences, Constellation Pharmaceuticals, NGM Biopharmaceuticals, and Sensei Biotherapeutics. J.S. and A.S. receive funding from BMS and Gritstone, are consultants for Turnstone, and perform fee-for-service assays for Neon. A.S. is a consultant for Gritstone. N.B. receives research funds from Novocure, Celldex, Ludwig institute, Genentech, Oncovir, Melanoma Research Alliance, Cancer Research Institute, Leukemia & Lymphoma Society, 485, NYSTEM, and Regeneron, and is on the advisory boards of Neon, Tempest, Checkpoint Sciences, Curevac, Primevax, Novartis, Array BioPharma, Roche, and Avidea. T.N.S. receives research funds from Merck KGaA, is consultant/advisory board member for Adaptive Biotechnologies, AIMM Therapeutics, Allogene Therapeutics, Merus, Neogene Therapeutics, Neon Therapeutics, Scenic Biotech, and Third Rock Ventures, and is a stockholder in AIMM Therapeutics, Allogene Therapeutics, BioNTech, Merus, Neogene Therapeutics, Scenic Biotech, and Third Rock Ventures Fund IV and V. A.R. has received honoraria from consulting with Amgen, Bristol-Myers Squibb, Chugai, Genentech, Merck, Novartis, Roche, and Sanofi, is or has been a member of the scientific advisory board, holds stock in Advaxis, Apricity, Arcus Biosciences, Bioncotech Therapeutics, Compugen, CytomX, Five Prime, FLX-Bio, ImaginAb, Isoplexis, Kite-Gilead, Lutris Pharma, Merus, PACT Pharma, Rgenix, and Tango Therapeutics, has received research funding from Agilent and from Bristol-Myers Squibb through Stand Up to Cancer (SU2C), and has received payment for licensing a patent on non-viral T cell gene editing to Arsenal. The remaining authors declare no conflicts of interest.

Attached Files

Supplemental Material - 1-s2.0-S0092867420311569-mmc1.xlsx

Supplemental Material - 1-s2.0-S0092867420311569-mmc2.xlsx

Supplemental Material - 1-s2.0-S0092867420311569-mmc3.xlsx

Supplemental Material - 1-s2.0-S0092867420311569-mmc4.xlsx

Supplemental Material - 1-s2.0-S0092867420311569-mmc5.xlsx

Supplemental Material - 1-s2.0-S0092867420311569-mmc6.xlsx

Supplemental Material - 1-s2.0-S0092867420311569-mmc7.xlsx

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Created:
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