Obesity Is Associated With Lower Tumor Oxidative Phosphorylation (Oxphos) In Metastatic Melanoma (Mm).

Abstract Immune checkpoint inhibitors (ICI) and BRAF targeted therapies improve overall survival (OS) for patients (pts) with MM, but treatment responses are heterogeneous. Recent data strongly implicates host factors in response and resistance to these agents. We and others have shown that overweight/obese BMI [OW/OB: body mass index (BMI≥25)] is associated with improved OS with both ICI and BRAF targeted therapies in MM pts. The biologic basis for this association is unknown. Thus, we examined the molecular and immune correlates of BMI in MM. In melanoma TCGA regionally metastatic specimens with available BMI (n=202), BMI was not associated with DNA mutations or copy number variations, nor with protein expression. To assess for associations with gene expression, we performed a gene set enrichment analysis (GSEA) on pooled data for cohorts of MM patients with RNAseq and BMI data (TCGA, n=202; MDACC, n=61; MIA, n=68; UCLA, n=26). Following batch correction, GSEA identified downregulation of OXPHOS and adipogenesis in tumors from OW/OB pts compared to normal (NL) BMI (BMI<25). Mass spectrometry of 36 MM specimens from the TCGA cohort confirmed downregulation of the TCA cycle intermediates citrate (p=0.01) and succinate (p<0.05) in OW/OB MM. Immunohistochemistry for key immune cell populations and checkpoints in the MIA and MDACC cohorts did not identify significant differences by BMI, consistent with the lack of difference in inflammatory pathways by gene expression. Finally, we evaluated associations of BMI with gut microbiome features in MM pts (n=272). OW/OB was associated with lower microbial alpha diversity vs. NL BMI (p=0.02), but no significant differences were observed in the composition of individual species. As increased microbiome diversity has been associated with improved outcomes with ICI in MM, this finding supports that changes in the microbiome are unlikely to explain the improved outcomes seen with ICI in OW/OB pts. In sum, our findings suggest that host energy balance influences tumor metabolism in MM, with downregulation of OXPHOS in MM from OB/OW pts, which may influence outcomes with targeted and immune therapies. These hypothesis generating findings suggest one possible mechanism underlying the obesity paradox observed in MM pts. Citation Format: Andrew W. Hahn, Mingchu Xu, Jun Li, Lauren E. Haydu, M.A. Wadud Khan, Tuba N. Gide, Alexander M. Menzies, Courtney W. Hudgens, Theodore S. Nowicki, Jeffrey E. Gershenwald, Antoni Ribas, Michael T. Tetzlaff, Alexander J. Lazar, James Willmott, Jennifer Wargo, Andrew Futreal, Jianhua Zhang, Michael A. Davies, Jennifer L. McQuade. Obesity is associated with lower tumor oxidative phosphorylation (OXPhos) in metastatic melanoma (MM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB208.