Proteomics of Melanoma Response to Immunotherapy Reveals Mitochondrial Dependence

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.

Multiplexed relative and absolute quantitative immunopeptidomics reveals MHC I repertoire alterations induced by CDK4/6 inhibition

“…Recently, high tumor antigen and metabolic protein expression levels have been shown to be predictive of checkpoint inhibitor response in melanoma, suggesting that CDK4/6i could be used in conjunction with checkpoint blockade or TIL-based therapies to increase tumor immunogenicity. 52 As an alternate therapeutic strategy, peptide antigens whose surface 17 expression was selectively increased by CDK4/6i could be utilized for targeted immunotherapy, either alone or in combination.…”

The immunological Warburg effect: Can a metabolic‐tumor‐stroma score (MeTS) guide cancer immunotherapy?

“…119,172 Accordingly, good response to immunotherapy was associated with enriched mitochondrial metabolism in melanoma patients. 173 Surprisingly, the opposite finding was reported regarding PD-1 blockade in a melanoma study showing that tumor oxygen consumption was associated with T cell exhaustion and progression under checkpoint blockade. 174 Nevertheless, the efficacy of checkpoint blockade was improved by LDH suppression in murine tumors.…”

“…Good response to checkpoint blockade a 84,119,173,175 Renal cell carcinoma Lower T cell infiltration, inferior response to checkpoint blockade 24,172 Colon cancer Lower CD8 T cell infiltration 25 Head and neck squamous cell carcinoma Lower CD8 T cell infiltration 26 Lung squamous cell carcinoma Lower CD8 T cell infiltration 26 Lung adenocarcinoma Lower T cell infiltration 55 Lung carcinoma Impaired anti-tumor T cell response 17 Prostate cancer Reduced anti-tumoral Th1 cells 115 a A contradictory finding by Najjar et al 174 who found high tumor OXPHOS as a barrier to checkpoint blockade.…”

Increasing Complexity to Simplify Clinical Care: High Resolution Mass Spectrometry as an Enabler of AI Guided Clinical and Therapeutic Monitoring

“…The accuracy and sensitivity of these machines has propelled HR/MS to be applied in fields such as proteomics and metabolomics. [ 128–130 ] HR/MS can utilize both the bottom‐up approach [ 131 ] as well as sequence intact proteins (top‐down approach). [ 132 ] Both these approaches complement each other and allow deeper understanding of protein expression profiles, leading to better diagnosis and classification of diseases.…”