Loss of Tumor-Infiltrating Lymphocytes and Poor Response to Immunotherapy in IDH GOF Mutant Melanoma

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Abstract

Recent innovations in melanoma treatment with immune checkpoint blockade (ICB) have improved overall outcomes for patients, however over 50% of patients still develop resistance to treatment. These patients either have intrinsic resistance, and never respond to therapy, or develop acquired resistance months or years into treatment. The mechanisms underlying ICB resistance remain poorly understood. Our data shows that isocitrate dehydrogenase gain of function (IDH GOF) mutant melanoma patients have a worse response to anti-PD1 immunotherapy. IDH mutations have been found to be oncogenic and associated with differential methylation in multiple cancers but are not yet characterized in human melanoma. Here, we investigate the clinical, immune, and transcriptional phenotypes of IDH GOF melanomas through analyses of clinical response, single-cell RNA sequencing, bulk RNA sequencing, and DNA methylation data. Single-cell data analysis shows decreased immune infiltrate and activity in the IDH GOF tumors. Bulk sequencing data demonstrates the association between IDH mutation, immune exclusion, and disruptions in global DNA methylation. The melanoma-derived genomic data presented supports previously described resistance mechanisms of IDH mutation in other cancer types and is the first demonstration of the role of IDH GOF in the human melanoma tumor microenvironment.

Authors

Emma Specht, Lakshmi Pakanati, Meng-Ju Wu, Russell W. Jenkins, Derek N. Effiom, Nabeel Bardeesy, Bradley E. Bernstein, Moshe Sade-Feldman, Christine G. Lian, Genevieve M. Boland, Elena Torlai Triglia, Sonia Cohen