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

Wells, Daniel K. and van Buuren, Marit M. and Dang, Kristen K. and Hubbard-Lucey, Vanessa M. and Sheehan, Kathleen C. F. and Campbell, Katie M. and Lamb, Andrew and Ward, Jeffrey P. and Sidney, John and Blazquez, Ana B. and Rech, Andrew J. and Zaretsky, Jesse M. and Comin-Anduix, Begonya and Ng, Alphonsus H. C. and Chour, William and Yu, Thomas V. and Rizvi, Hira and Chen, Jia M. and Manning, Patrice and Steiner, Gabriela M. and Doan, Xengie C. and Merghoub, Taha and Guinney, Justin and Kolom, Adam and Selinsky, Cheryl and Ribas, Antoni and Hellmann, Matthew D. and Hacohen, Nir and Sette, Alessandro and Heath, James R. and Bhardwaj, Nina and Ramsdell, Fred and Schreiber, Robert D. and Schumacher, Ton N. and Kvistborg, Pia and Defranoux, Nadine A. and Khan, Aly A. and Lugade, Amit and Mijalkovic Lazic, Ana M. and Frentzen, Angela A. Elizabeth and Tadmor, Arbel D. and Sasson, Ariella S. and Rao, Arjun A. and Pei, Baikang and Schrörs, Barbara and Berent-Maoz, Beata and Carreno, Beatriz M. and Song, Bin and Peters, Bjoern and Li, Bo and Higgs, Brandon W. and Stevenson, Brian J. and Iseli, Christian and Miller, Christopher A. and Morehouse, Christopher A. and Melief, Cornelis J. M. and Puig-Saus, Cristina and van Beek, Daphne and Balli, David and Gfeller, David and Haussler, David and Jäger, Dirk and Cortes, Eduardo and Esaulova, Ekaterina and Sherafat, Elham and Arcila, Francisco and Bartha, Gabor and Liu, Geng and Coukos, George and Richard, Guilhem and Chang, Han and Si, Han and Zörnig, Inka and Xenarios, Ioannis and Mandoiu, Ion and Kooi, Irsan and Conway, James P. and Kessler, Jan H. and Greenbaum, Jason A. and Perera, Jason F. and Harris, Jason and Hundal, Jasreet and Shelton, Jennifer M. and Wang, Jianmin and Wang, Jiaqian and Greshock, Joel and Blake, Jonathon and Szustakowski, Joseph and Kodysh, Julia and Forman, Juliet and Wei, Lei and Lee, Leo J. and Fanchi, Lorenzo F. and Slagter, Maarten and Lang, Maren and Mueller, Markus and Lower, Martin and Vormehr, Mathias and Artyomov, Maxim N. and Kuziora, Michael and Princiotta, Michael and Bassani-Sternberg, Michal and Macabali, Mignonette and Kojicic, Milica R. and Yang, Naibo and Raicevic, Nevena M. Ilic and Guex, Nicolas and Robine, Nicolas and Halama, Niels and Skundric, Nikola M. and Milicevic, Ognjen S. and Gellert, Pascal and Jongeneel, Patrick and Charoentong, Pornpimol and Srivastava, Pramod K. and Tanden, Prateek and Shah, Priyanka and Hu, Qiang and Gupta, Ravi and Chen, Richard and Petit, Robert and Ziman, Robert and Hilker, Rolf and Shukla, Sachet A. and Al Seesi, Sahar and Boyle, Sean M. and Qiu, Si and Sarkizova, Siranush and Salama, Sofie and Liu, Song and Wu, Song and Sridhar, Sriram and Ketelaars, Steven L. C. and Jhunjhunwala, Suchit and Shcheglova, Tatiana and Schuepbach, Thierry and Creasy, Todd H. and Josipovic, Veliborka and Kovacevic, Vladimir B. and Fu, Weixuan and Krebber, Willem-Jan and Hsu, Yi-Hsiang and Sebastian, Yinong and Kosaloglu-Yalcin, Zeynep and Huang, Zhiqin (2020) Key Parameters of Tumor Epitope Immunogenicity Revealed Through a Consortium Approach Improve Neoantigen Prediction. Cell, 183 (3). pp. 818-834. ISSN 0092-8674.

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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.

Item Type:Article
Related URLs:
URLURL TypeDescription
Wells, Daniel K.0000-0003-2463-3139
Dang, Kristen K.0000-0002-7512-4476
Sheehan, Kathleen C. F.0000-0002-3357-8285
Campbell, Katie M.0000-0001-6491-4432
Ward, Jeffrey P.0000-0002-9707-895X
Zaretsky, Jesse M.0000-0002-4889-2648
Ng, Alphonsus H. C.0000-0003-0074-4598
Chour, William0000-0003-1817-0123
Yu, Thomas V.0000-0002-5841-0198
Guinney, Justin0000-0003-1477-1888
Kolom, Adam0000-0003-3170-8231
Selinsky, Cheryl0000-0002-8792-055X
Hellmann, Matthew D.0000-0002-2670-9777
Schumacher, Ton N.0000-0003-0517-8804
Kvistborg, Pia0000-0002-4988-608X
Defranoux, Nadine A.0000-0002-6825-5531
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.
Funding AgencyGrant Number
Parker Institute for Cancer ImmunotherapyUNSPECIFIED
NIHR21 AI34127
NIH Predoctoral FellowshipGM08042
NIH Predoctoral FellowshipT32CA009120
Cancer Research InstituteUNSPECIFIED
Queen Wilhelmina Cancer Research AwardUNSPECIFIED
Subject Keywords:immunotherapy; neoantigen; immunogenomics; epitope; TESLA; immunogenicity
Issue or Number:3
Record Number:CaltechAUTHORS:20201019-121956456
Persistent URL:
Official Citation:Daniel K. Wells, Marit M. van Buuren, Kristen K. Dang, Vanessa M. Hubbard-Lucey, Kathleen C.F. Sheehan, Katie M. Campbell, Andrew Lamb, Jeffrey P. Ward, John Sidney, Ana B. Blazquez, Andrew J. Rech, Jesse M. Zaretsky, Begonya Comin-Anduix, Alphonsus H.C. Ng, William Chour, Thomas V. Yu, Hira Rizvi, Jia M. Chen, Patrice Manning, Gabriela M. Steiner, Xengie C. Doan, Aly A. Khan, Amit Lugade, Ana M. Mijalkovic Lazic, Angela A. Elizabeth Frentzen, Arbel D. Tadmor, Ariella S. Sasson, Arjun A. Rao, Baikang Pei, Barbara Schrörs, Beata Berent-Maoz, Beatriz M. Carreno, Bin Song, Bjoern Peters, Bo Li, Brandon W. Higgs, Brian J. Stevenson, Christian Iseli, Christopher A. Miller, Christopher A. Morehouse, Cornelis J.M. Melief, Cristina Puig-Saus, Daphne van Beek, David Balli, David Gfeller, David Haussler, Dirk Jäger, Eduardo Cortes, Ekaterina Esaulova, Elham Sherafat, Francisco Arcila, Gabor Bartha, Geng Liu, George Coukos, Guilhem Richard, Han Chang, Han Si, Inka Zörnig, Ioannis Xenarios, Ion Mandoiu, Irsan Kooi, James P. Conway, Jan H. Kessler, Jason A. Greenbaum, Jason F. Perera, Jason Harris, Jasreet Hundal, Jennifer M. Shelton, Jianmin Wang, Jiaqian Wang, Joel Greshock, Jonathon Blake, Joseph Szustakowski, Julia Kodysh, Juliet Forman, Lei Wei, Leo J. Lee, Lorenzo F. Fanchi, Maarten Slagter, Maren Lang, Markus Mueller, Martin Lower, Mathias Vormehr, Maxim N. Artyomov, Michael Kuziora, Michael Princiotta, Michal Bassani-Sternberg, Mignonette Macabali, Milica R. Kojicic, Naibo Yang, Nevena M. Ilic Raicevic, Nicolas Guex, Nicolas Robine, Niels Halama, Nikola M. Skundric, Ognjen S. Milicevic, Pascal Gellert, Patrick Jongeneel, Pornpimol Charoentong, Pramod K. Srivastava, Prateek Tanden, Priyanka Shah, Qiang Hu, Ravi Gupta, Richard Chen, Robert Petit, Robert Ziman, Rolf Hilker, Sachet A. Shukla, Sahar Al Seesi, Sean M. Boyle, Si Qiu, Siranush Sarkizova, Sofie Salama, Song Liu, Song Wu, Sriram Sridhar, Steven L.C. Ketelaars, Suchit Jhunjhunwala, Tatiana Shcheglova, Thierry Schuepbach, Todd H. Creasy, Veliborka Josipovic, Vladimir B. Kovacevic, Weixuan Fu, Willem-Jan Krebber, Yi-Hsiang Hsu, Yinong Sebastian, Zeynep Kosaloglu- Yalcin, Zhiqin Huang, Taha Merghoub, Justin Guinney, Adam Kolom, Cheryl Selinsky, Antoni Ribas, Matthew D. Hellmann, Nir Hacohen, Alessandro Sette, James R. Heath, Nina Bhardwaj, Fred Ramsdell, Robert D. Schreiber, Ton N. Schumacher, Pia Kvistborg, Nadine A. Defranoux, Key Parameters of Tumor Epitope Immunogenicity Revealed Through a Consortium Approach Improve Neoantigen Prediction, Cell, Volume 183, Issue 3, 2020, Pages 818-834.e13, ISSN 0092-8674, (
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ID Code:106147
Deposited By: Tony Diaz
Deposited On:20 Oct 2020 18:48
Last Modified:30 Oct 2020 21:53

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