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

Sep 23, 2026

Uploaded by Franzy

Immune checkpoint blockade for advanced melanoma improves outcomes, yet most patients develop resistance, either intrinsic or acquired during treatment. This study evaluates how isocitrate dehydrogenase gain-of-function (IDH GOF) mutant melanoma influences clinical, immune, and transcriptional features. Analyses using clinical response data, single-cell RNA-seq, bulk RNA-seq, and DNA methylation show reduced immune infiltration and activity in IDH GOF tumors, alongside immune exclusion and global DNA methylation disruptions that align with known resistance mechanisms.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages16

Reading Time40 min

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Introduction

RESE AR CH ARTICLE Loss of tumor-infiltrating lymphocytes and poor response to immunotherapy in IDH GOF mutant melanoma Emma Specht,1,2 Lakshmi Pakanati,1 Meng-Ju Wu,2,3,4 Russell W. Jenkins,2,3,5 Derek N. Effiom,1 Nabeel Bardeesy,2,3 Bradley E. Bernstein,6,7 Moshe Sade-Feldman,2,3 Christine G. Lian,8 Genevieve M. Boland,1,2,3 Elena Torlai Triglia,3,9 and Sonia Cohen1 1Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. 2Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA. 3Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. 4Division of Gastroenterology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA. 5Division of Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA. 6Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. 7Departments of Cell Biology and 8Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA. 9School of Biological and Behavioural Sciences, Queen Mary University of London, London, United Kingdom. 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 ofthe role of IDH GOF in the human melanoma tumor microenvironment. Copyright: © 2026, Specht et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License. Authorship note: ETT and SC are co-senior authors. Submitted: May 15, 2025 Accepted: March 24, 2026 Published: April 9, 2026 Reference information: JCI Insight. 2026;11(10):e195384 . [https://doi.org/10.1172/jci](https://doi.org/10.1172/jci). insight.195384 . Introduction Immunotherapy, including immune checkpoint blockade (ICB) and tumor-infiltrating lymphocyte (TIL) therapy, has become the standard of care for the treatment of advanced melanoma. Unfortunately, the majority of patients demonstrate resistance to treatment with single-agent regimens — up to 56% of patients treated with nivolumab are nonresponders to therapy at 5 years (1) . Even with novel combination therapies, over 50% of patients with melanoma have de novo or acquired resistance to therapy and ultimately die of their disease (2) . Those with intrinsic resistance to single-agent immunotherapy show limited response at 6 months (3) . Other patients with acquired resistance will show an initial favorable response to therapy but later progress. An increased understanding of these resistance mechanisms and their link to genetic alterations will allow for better outcomes for patients with melanoma through tailored therape

FAQs

What problem does the study address in melanoma immunotherapy?

The study addresses why many patients resist immune checkpoint blockade, including both intrinsic nonresponse and acquired resistance over time.

What is the main finding about IDH GOF mutant melanoma?

IDH GOF mutant melanoma shows a worse response to anti-PD1 immunotherapy, with decreased immune infiltrate and activity.

Which data types are used to characterize IDH GOF tumors?

The study combines clinical response analyses with single-cell RNA-seq, bulk RNA-seq, and DNA methylation to link immune phenotypes and methylation disruptions to IDH mutations.

Sep 23, 2026

Uploaded by Franzy