Proteomics of Melanoma Response to Immunotherapy Reveals Mitochondrial Dependence

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


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.

Publication types

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

MeSH terms

  • Adoptive Transfer / methods
  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Cell Line, Tumor
  • Cohort Studies
  • Female
  • Humans
  • Immunotherapy / methods*
  • Lipid Metabolism / immunology
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Male
  • Melanoma / metabolism*
  • Melanoma / therapy*
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Mitochondria / metabolism*
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Proteomics / methods*
  • Skin Neoplasms / metabolism*
  • Skin Neoplasms / therapy*
  • T-Lymphocytes / immunology
  • Treatment Outcome
  • Young Adult


  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor