Loss of tumor-infiltrating lymphocytes and poor response to immunotherapy in IDH GOF mutant melanoma
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
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
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Research Article Genetics Immunology Oncology

Loss of tumor-infiltrating lymphocytes and poor response to immunotherapy in IDH GOF mutant melanoma

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 show that patients with isocitrate dehydrogenase gain-of-function (IDH GOF) mutant melanoma 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-seq, bulk RNA-seq, and DNA methylation data. Single-cell data analysis showed decreased immune infiltrate and activity in the IDH GOF tumors. Bulk sequencing data demonstrated the association among IDH mutation, immune exclusion, and disruptions in global DNA methylation. The melanoma-derived genomic data presented support previously described resistance mechanisms of IDH mutation in other cancer types and is the first demonstration to our knowledge 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

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Figure 4

IDH GOF melanoma tumors are globally silenced and may promote resistance through dsDNA-mediated viral mimicry.

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IDH GOF melanoma tumors are globally silenced and may promote resistanc...
(A) Volcano plot of the differentially expressed genes across single-cell melanoma conditions with significantly upregulated genes in red and significantly downregulated genes in blue. All labeled points refer to gene labels. For visualization purposes, 7 genes with log2FC < 0 were excluded from the volcano plot (but included in the analysis). Pseudobulk analysis of tumor cells from the single-cell samples demonstrated global gene repression. (B) Volcano plot of the differentially expressed genes across TCGA conditions with significantly upregulated genes in red and significantly downregulated genes in blue. For visualization purposes, 8 genes with log2FC < 0 were excluded from the plot (but included in the analysis). Bulk RNA-sequencing data from TCGA mirror the global gene repression. (C) 96 overlapping significantly differentially expressed genes between the single-cell and TCGA cohort were identified, many of which fell within the immune-related GO terms (blue dots). (D) Heatmap showing expression of gene sets with higher expression in red and lower expression in blue. Volcano plots show specific log2FC and adjusted P values for each gene in the set between conditions. IFN-response Hallmark Genes sets were overall downregulated in IDH pseudobulk single-cell data. Omitted for visualization purposes was MX2 at coordinate (log2FC = –8.0522, Padj = 1.02029e-19). Viral regulation and cytosolic dsDNA sensing were also downregulated in IDH GOF mutants.