Combined analysis of antigen presentation and T-cell recognition reveals restricted immune responses in melanoma

Shelly Kalaora, Yochai Wolf, Tali Feferman, Eilon Barnea, Erez Greenstein, Dan Reshef, Itay Tirosh, Alexandre Reuben, Sushant Patkar, Ronen Levy, Juliane Quinkhardt, Tana Omokoko, Nouar Qutob, Ofra Golani, Jianhua Zhang, Xizeng Mao, Xingzhi Song, Chantale Bernatchez, Cara Haymaker, Marie Andrée ForgetCaitlin Creasy, Polina Greenberg, Brett W. Carter, Zachary A. Cooper, Steven A. Rosenberg, Michal Lotem, Ugur Sahin, Guy Shakhar, Eytan Ruppin, Jennifer A. Wargo, Nir Friedman, Arie Admon, Yardena Samuels*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

The quest for tumor-associated antigens (TAA) and neoantigens is a major focus of cancer immunotherapy. Here, we combine a neoantigen prediction pipeline and human leukocyte antigen (HLA) peptidomics to identify TAAs and neoantigens in 16 tumors derived from seven patients with melanoma and characterize their interactions with their tumor-infiltrating lymphocytes (TIL). Our investigation of the antigenic and T-cell landscapes encompassing the TAA and neoantigen signatures, their immune reactivity, and their corresponding T-cell identities provides the first comprehensive analysis of cancer cell T-cell cosignatures, allowing us to discover remarkable antigenic and TIL similarities between metastases from the same patient. Furthermore, we reveal that two neoantigen-specific clonotypes killed 90% of autologous melanoma cells, both in vitro and in vivo, showing that a limited set of neoantigen-specific T cells may play a central role in melanoma tumor rejection. Our findings indicate that combining HLA peptidomics with neoantigen predictions allows robust identification of targetable neoantigens, which could successfully guide personalized cancer immunotherapies. SIGNIFICANCE: As neoantigen targeting is becoming more established as a powerful therapeutic approach, investigating these molecules has taken center stage. Here, we show that a limited set of neoantigen-specific T cells mediates tumor rejection, suggesting that identifying just a few antigens and their corresponding T-cell clones could guide personalized immunotherapy.

Original languageEnglish
Pages (from-to)1366-1375
Number of pages10
JournalCancer Discovery
Volume8
Issue number11
DOIs
StatePublished - Nov 2018
Externally publishedYes

Funding

FundersFunder number
European Union’s Horizon 2020 research and innovation program
Feinberg School Dean’s Scholarship
Knell Family
National Institutes of Health
National Cancer Institute
Melanoma Research Alliance402024
Seventh Framework Programme335377, 754282
European Research Council
Israel Science Foundation696/17
Horizon 2020

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