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Cell. 2019 Sep 19;179(1):236-250.e18. doi: 10.1016/j.cell.2019.08.012. Epub 2019 Sep 5.

Proteomics of Melanoma Response to Immunotherapy Reveals Mitochondrial Dependence.

Author information

1
Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel-Aviv 6997801, Israel.
2
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.
3
NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
4
Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
5
Ella Lemelbaum Institute of Immuno-Oncology, Sheba Medical Center, Tel Hashomer 5265601, Israel.
6
Institute of Pathology, Sheba Medical Center, Tel Hashomer 5265601, Israel.
7
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.
8
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.
9
Institute of Pathology, Sheba Medical Center, Tel Hashomer 5265601, Israel; The Sackler School of Medicine, Tel Aviv University, Tel-Aviv 6997801, Israel.
10
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.
11
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.

Abstract

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.

KEYWORDS:

anti-PD-1; cancer metabolism; immune checkpoint inhibitors; immunotherapy; lipid metabolism; mass spectrometry; melanoma; mitochondrial metabolism; proteomics; tumor-infiltrating lymphocytes

PMID:
31495571
DOI:
10.1016/j.cell.2019.08.012

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