PMID- 30209080
OWN - NLM
STAT- MEDLINE
DCOM- 20191108
LR  - 20200309
IS  - 2159-8290 (Electronic)
IS  - 2159-8274 (Print)
IS  - 2159-8274 (Linking)
VI  - 8
IP  - 11
DP  - 2018 Nov
TI  - Combined Analysis of Antigen Presentation and T-cell Recognition Reveals 
      Restricted Immune Responses in Melanoma.
PG  - 1366-1375
LID - 10.1158/2159-8290.CD-17-1418 [doi]
AB  - 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. 
      (c)2018 AACR. This article is highlighted in the In This Issue feature, p. 1333.
CI  - (c)2018 American Association for Cancer Research.
FAU - Kalaora, Shelly
AU  - Kalaora S
AD  - Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, 
      Israel.
FAU - Wolf, Yochai
AU  - Wolf Y
AD  - Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, 
      Israel.
FAU - Feferman, Tali
AU  - Feferman T
AD  - Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
FAU - Barnea, Eilon
AU  - Barnea E
AD  - Department of Biology, Technion, Haifa, Israel.
FAU - Greenstein, Erez
AU  - Greenstein E
AD  - Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
FAU - Reshef, Dan
AU  - Reshef D
AD  - Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
FAU - Tirosh, Itay
AU  - Tirosh I
AD  - Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, 
      Israel.
FAU - Reuben, Alexandre
AU  - Reuben A
AUID- ORCID: 0000-0003-4510-0382
AD  - Departments of Surgical Oncology and Genomic Medicine, The University of Texas MD 
      Anderson Cancer Center, Houston, Texas.
FAU - Patkar, Sushant
AU  - Patkar S
AD  - Cancer Data Science Lab, National Cancer Institute, NIH, Rockville, Maryland.
FAU - Levy, Ronen
AU  - Levy R
AD  - Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, 
      Israel.
FAU - Quinkhardt, Juliane
AU  - Quinkhardt J
AD  - BioNTech Cell & Gene Therapies GmbH, Mainz, Germany.
FAU - Omokoko, Tana
AU  - Omokoko T
AD  - BioNTech Cell & Gene Therapies GmbH, Mainz, Germany.
FAU - Qutob, Nouar
AU  - Qutob N
AD  - Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, 
      Israel.
FAU - Golani, Ofra
AU  - Golani O
AD  - Department of Life Sciences Core Facilities, Weizmann Institute of Science, 
      Rehovot, Israel.
FAU - Zhang, Jianhua
AU  - Zhang J
AD  - Departments of Surgical Oncology and Genomic Medicine, The University of Texas MD 
      Anderson Cancer Center, Houston, Texas.
FAU - Mao, Xizeng
AU  - Mao X
AD  - Departments of Surgical Oncology and Genomic Medicine, The University of Texas MD 
      Anderson Cancer Center, Houston, Texas.
FAU - Song, Xingzhi
AU  - Song X
AD  - Departments of Surgical Oncology and Genomic Medicine, The University of Texas MD 
      Anderson Cancer Center, Houston, Texas.
FAU - Bernatchez, Chantale
AU  - Bernatchez C
AD  - Department of Melanoma Medical Oncology, The University of Texas MD Anderson 
      Cancer Center, Houston, Texas.
FAU - Haymaker, Cara
AU  - Haymaker C
AD  - Department of Melanoma Medical Oncology, The University of Texas MD Anderson 
      Cancer Center, Houston, Texas.
FAU - Forget, Marie-Andree
AU  - Forget MA
AD  - Department of Melanoma Medical Oncology, The University of Texas MD Anderson 
      Cancer Center, Houston, Texas.
FAU - Creasy, Caitlin
AU  - Creasy C
AUID- ORCID: 0000-0002-6271-0337
AD  - Department of Melanoma Medical Oncology, The University of Texas MD Anderson 
      Cancer Center, Houston, Texas.
FAU - Greenberg, Polina
AU  - Greenberg P
AD  - Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, 
      Israel.
FAU - Carter, Brett W
AU  - Carter BW
AD  - Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer 
      Center, Houston, Texas.
FAU - Cooper, Zachary A
AU  - Cooper ZA
AUID- ORCID: 0000-0003-1059-0940
AD  - Departments of Surgical Oncology and Genomic Medicine, The University of Texas MD 
      Anderson Cancer Center, Houston, Texas.
FAU - Rosenberg, Steven A
AU  - Rosenberg SA
AD  - National Cancer Institute, NIH, Maryland.
FAU - Lotem, Michal
AU  - Lotem M
AD  - Sharett Institute of Oncology, Hadassah Medical School, Jerusalem, Israel.
FAU - Sahin, Ugur
AU  - Sahin U
AD  - TRON-Translational Oncology at the University Medical Center of Johannes 
      Gutenberg University GmbH, Mainz, Germany.
FAU - Shakhar, Guy
AU  - Shakhar G
AD  - Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
FAU - Ruppin, Eytan
AU  - Ruppin E
AD  - Cancer Data Science Lab, National Cancer Institute, NIH, Rockville, Maryland.
FAU - Wargo, Jennifer A
AU  - Wargo JA
AD  - Departments of Surgical Oncology and Genomic Medicine, The University of Texas MD 
      Anderson Cancer Center, Houston, Texas.
FAU - Friedman, Nir
AU  - Friedman N
AUID- ORCID: 0000-0002-1078-3921
AD  - Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
FAU - Admon, Arie
AU  - Admon A
AUID- ORCID: 0000-0003-0504-3950
AD  - Department of Biology, Technion, Haifa, Israel.
FAU - Samuels, Yardena
AU  - Samuels Y
AUID- ORCID: 0000-0002-3349-7266
AD  - Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, 
      Israel. yardena.samuels@weizmann.ac.il.
LA  - eng
GR  - Z01 BC010984-01/Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20180912
PL  - United States
TA  - Cancer Discov
JT  - Cancer discovery
JID - 101561693
RN  - 0 (Antigens, Neoplasm)
RN  - 0 (Histocompatibility Antigens Class I)
SB  - IM
MH  - Animals
MH  - Antigen Presentation/*immunology
MH  - Antigens, Neoplasm/*immunology/metabolism
MH  - Histocompatibility Antigens Class I/*immunology/metabolism
MH  - Humans
MH  - Lymphocytes, Tumor-Infiltrating/*immunology
MH  - Melanoma/*immunology/metabolism/pathology
MH  - Mice
MH  - Mice, Inbred NOD
MH  - Mice, SCID
MH  - T-Lymphocytes/*immunology/metabolism
MH  - Tumor Cells, Cultured
MH  - Xenograft Model Antitumor Assays
PMC - PMC6453138
MID - NIHMS1001262
COIS- Disclosure of Potential Conflicts of Interest M. Lotem has received honoraria 
      from the speakers bureaus of MSD and BMS and is a consultant/advisory board 
      member for MSD. U. Sahin is CEO at BioNTech, reports receiving a commercial 
      research grant from BioNTech, and has ownership interest (including stock, 
      patents, etc.) in BioNTech. J.A. Wargo has received honoraria from the speakers 
      bureaus of Dava Oncology and Illumina and is a consultant/advisory board member 
      for BMS, Novartis, Genentech, AstraZeneca, Illumina, and Merck. No potential 
      conflicts of interest were disclosed by the other authors.
EDAT- 2018/09/14 06:00
MHDA- 2019/11/09 06:00
PMCR- 2019/04/08
CRDT- 2018/09/14 06:00
PHST- 2017/12/18 00:00 [received]
PHST- 2018/02/26 00:00 [revised]
PHST- 2018/08/16 00:00 [accepted]
PHST- 2018/09/14 06:00 [pubmed]
PHST- 2019/11/09 06:00 [medline]
PHST- 2018/09/14 06:00 [entrez]
PHST- 2019/04/08 00:00 [pmc-release]
AID - 2159-8290.CD-17-1418 [pii]
AID - 10.1158/2159-8290.CD-17-1418 [doi]
PST - ppublish
SO  - Cancer Discov. 2018 Nov;8(11):1366-1375. doi: 10.1158/2159-8290.CD-17-1418. Epub 
      2018 Sep 12.