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Cancer Discov. 2018 Nov;8(11):1366-1375. doi: 10.1158/2159-8290.CD-17-1418. Epub 2018 Sep 12.

Combined Analysis of Antigen Presentation and T-cell Recognition Reveals Restricted Immune Responses in Melanoma.

Author information

1
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
2
Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
3
Department of Biology, Technion, Haifa, Israel.
4
Departments of Surgical Oncology and Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
5
Cancer Data Science Lab, National Cancer Institute, NIH, Rockville, Maryland.
6
BioNTech Cell & Gene Therapies GmbH, Mainz, Germany.
7
Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel.
8
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
9
Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
10
National Cancer Institute, NIH, Maryland.
11
Sharett Institute of Oncology, Hadassah Medical School, Jerusalem, Israel.
12
TRON-Translational Oncology at the University Medical Center of Johannes Gutenberg University GmbH, Mainz, Germany.
13
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. yardena.samuels@weizmann.ac.il.
#
Contributed equally

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. Cancer Discov; 8(11); 1366-75. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 1333.

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