Proteomics of Melanoma Response to Immunotherapy Reveals Mitochondrial Dependence.


Journal

Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066

Informations de publication

Date de publication:
19 09 2019
Historique:
received: 22 03 2019
revised: 24 06 2019
accepted: 06 08 2019
pubmed: 10 9 2019
medline: 9 6 2020
entrez: 10 9 2019
Statut: ppublish

Résumé

Immunotherapy has revolutionized cancer treatment, yet most patients do not respond. Here, we investigated mechanisms of response by profiling the proteome of clinical samples from advanced stage melanoma patients undergoing either tumor infiltrating lymphocyte (TIL)-based or anti- programmed death 1 (PD1) immunotherapy. Using high-resolution mass spectrometry, we quantified over 10,300 proteins in total and ∼4,500 proteins across most samples in each dataset. Statistical analyses revealed higher oxidative phosphorylation and lipid metabolism in responders than in non-responders in both treatments. To elucidate the effects of the metabolic state on the immune response, we examined melanoma cells upon metabolic perturbations or CRISPR-Cas9 knockouts. These experiments indicated lipid metabolism as a regulatory mechanism that increases melanoma immunogenicity by elevating antigen presentation, thereby increasing sensitivity to T cell mediated killing both in vitro and in vivo. Altogether, our proteomic analyses revealed association between the melanoma metabolic state and the response to immunotherapy, which can be the basis for future improvement of therapeutic response.

Identifiants

pubmed: 31495571
pii: S0092-8674(19)30900-6
doi: 10.1016/j.cell.2019.08.012
pmc: PMC7993352
mid: NIHMS1654251
pii:
doi:

Substances chimiques

PDCD1 protein, human 0
Programmed Cell Death 1 Receptor 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

236-250.e18

Subventions

Organisme : NCI NIH HHS
ID : R01 CA216101
Pays : United States

Commentaires et corrections

Type : CommentIn

Informations de copyright

Copyright © 2019 Elsevier Inc. All rights reserved.

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Auteurs

Michal Harel (M)

Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel-Aviv 6997801, Israel.

Rona Ortenberg (R)

Ella Lemelbaum Institute of Immuno-Oncology, Sheba Medical Center, Tel Hashomer 5265601, Israel; Department of Clinical Immunology and Microbiology, Sackler School of Medicine, Tel Aviv University, Tel-Aviv 6997801, Israel.

Siva Karthik Varanasi (SK)

NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.

Kailash Chandra Mangalhara (KC)

Salk Institute for Biological Studies, La Jolla, CA 92037, USA.

Mariya Mardamshina (M)

Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel-Aviv 6997801, Israel.

Ettai Markovits (E)

Ella Lemelbaum Institute of Immuno-Oncology, Sheba Medical Center, Tel Hashomer 5265601, Israel; Department of Clinical Immunology and Microbiology, Sackler School of Medicine, Tel Aviv University, Tel-Aviv 6997801, Israel.

Erez N Baruch (EN)

Ella Lemelbaum Institute of Immuno-Oncology, Sheba Medical Center, Tel Hashomer 5265601, Israel; Department of Clinical Immunology and Microbiology, Sackler School of Medicine, Tel Aviv University, Tel-Aviv 6997801, Israel.

Victoria Tripple (V)

NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.

May Arama-Chayoth (M)

Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel-Aviv 6997801, Israel.

Eyal Greenberg (E)

Ella Lemelbaum Institute of Immuno-Oncology, Sheba Medical Center, Tel Hashomer 5265601, Israel.

Anjana Shenoy (A)

Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel-Aviv 6997801, Israel.

Ruveyda Ayasun (R)

NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.

Naama Knafo (N)

Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel-Aviv 6997801, Israel.

Shihao Xu (S)

NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.

Liat Anafi (L)

Institute of Pathology, Sheba Medical Center, Tel Hashomer 5265601, Israel.

Gali Yanovich-Arad (G)

Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel-Aviv 6997801, Israel.

Georgina D Barnabas (GD)

Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel-Aviv 6997801, Israel.

Shira Ashkenazi (S)

Ella Lemelbaum Institute of Immuno-Oncology, Sheba Medical Center, Tel Hashomer 5265601, Israel; Department of Clinical Immunology and Microbiology, Sackler School of Medicine, Tel Aviv University, Tel-Aviv 6997801, Israel.

Michal J Besser (MJ)

Ella Lemelbaum Institute of Immuno-Oncology, Sheba Medical Center, Tel Hashomer 5265601, Israel; Department of Clinical Immunology and Microbiology, Sackler School of Medicine, Tel Aviv University, Tel-Aviv 6997801, Israel.

Jacob Schachter (J)

Ella Lemelbaum Institute of Immuno-Oncology, Sheba Medical Center, Tel Hashomer 5265601, Israel; The Sackler School of Medicine, Tel Aviv University, Tel-Aviv 6997801, Israel.

Marcus Bosenberg (M)

Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA; Yale Comprehensive Cancer Center, New Haven, CT 06510, USA; Department of Dermatology, Yale University School of Medicine, New Haven, CT 06510, USA.

Gerald S Shadel (GS)

Salk Institute for Biological Studies, La Jolla, CA 92037, USA.

Iris Barshack (I)

Institute of Pathology, Sheba Medical Center, Tel Hashomer 5265601, Israel; The Sackler School of Medicine, Tel Aviv University, Tel-Aviv 6997801, Israel.

Susan M Kaech (SM)

NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.

Gal Markel (G)

Ella Lemelbaum Institute of Immuno-Oncology, Sheba Medical Center, Tel Hashomer 5265601, Israel; Department of Clinical Immunology and Microbiology, Sackler School of Medicine, Tel Aviv University, Tel-Aviv 6997801, Israel. Electronic address: markel@post.tau.ac.il.

Tamar Geiger (T)

Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel-Aviv 6997801, Israel. Electronic address: geiger@tauex.tau.ac.il.

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