IRF2 loss is associated with reduced MHC I pathway transcripts in subsets of most human cancers and causes resistance to checkpoint immunotherapy in human and mouse melanomas

Sep 21, 2026

Uploaded by Riley

Cancers progress by escaping elimination by CD8 T cells, often through reduced expression of MHC I molecules. This study examines whether specific mechanisms drive MHC I loss across cancer types and whether such loss is reversible. Bioinformatics and ChIP-seq analyses linked reduced IRF2 to lower MHC I pathway gene transcription in tumor subsets. CRISPR editing in patient-derived and mouse melanomas showed that IRF2 loss reduces MHC I surface complexes, diminishes Caspase 7, and induces resistance to checkpoint immunotherapy.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages16

Reading Time40 min

AccessFree to download

Abstract

Background

Methods

Results

Conclusions

Introduction

Tumor immune evasion and adaptive immunity

CD8 T cell recognition via MHC I

Sari et al. J Exp Clin Cancer Res (2024) 43:276 [https://doi.org/10.1186/s13046-024-03187-5](https://doi.org/10.1186/s13046-024-03187-5) Journal of Experimental & Clinical Cancer Research RESEARCH Open Access IRF2 loss is associated with reduced MHC I pathway transcripts in subsets of most human cancers and causes resistance to checkpoint immunotherapy in human and mouse melanomas G. Sari 1, K. Dhatchinamoorthy 1†, L. Orellano‑Ariza 1†, L. M. Ferreira2, M. A. Brehm2 and K. Rock 1* Abstract Background In order for cancers to progress, they must evade elimination by CD8 T cells or other immune mecha‑ nisms. CD8 T cells recognize and kill tumor cells that display immunogenic tumor peptides bound to MHC I mol‑ ecules. One of the ways that cancers can escape such killing is by reducing expression of MHC I molecules, and loss of MHC I is frequently observed in tumors. There are multiple different mechanisms that can underly the loss of MHCI complexes on tumor and it is currently unclear whether there are particular mechanisms that occur frequently and, if so, in what types of cancers. Also of importance to know is whether the loss of MHC I is reversible and how such loss and/or its restoration would impact responses to immunotherapy. Here, we investigate these issues for loss of IRF1 and IRF2, which are transcription factors that drive expression of MHC I pathway genes and some killing mechanisms. Methods Bioinformatics analyses of IRF2 and IRF2‑dependent gene transcripts were performed for all human cancers in the TCGA RNAseq database. IRF2 protein‑DNA‑binding was analyzed in ChIPseq databases. CRISRPcas9 was used to knock out IRF1 and IRF2 genes in human and mouse melanoma cells and the resulting phenotypes were analyzed in vitro and in vivo. Results Transcriptomic analysis revealed that IRF2 expression was reduced in a substantial subset of cases in almost all types of human cancers. When this occurred there was a corresponding reduction in the expression of IRF2‑ regulated genes that were needed for CD8 T cell recognition. To test cause and effect for these IRF2 correlationsand the consequences of IRF2 loss, we gene‑edited IRF2 in a patient‑derived melanoma and a mouse melanoma. The IRF2 gene‑edited melanomas had reduced expression of transcripts for genes in the MHC I pathway and decreased levels of MHC I complexes on the cell surface. Levels of Caspase 7, an IRF2 target gene involved in CD8 T cell kill‑ ing of tumors, were also reduced. This loss of IRF2 caused both human and mouse melanomas to become resistant to immunotherapy with a checkpoint inhibitor. Importantly, these effects were reversible. Stimulation of the IRF2‑ deficient melanomas with interferon induced the expression of a functionally homologous transcription factor, IRF1, which then restored the MHC I pathway and responsiveness to CPI. †K. Dhatchinamoorthy and L. Orellano‑Ariza contributed equally to this work. *Correspondence: K. Rock [Kenneth.Rock@umassmed.edu](Kenneth.Rock@umassmed.edu) Full list of author information is available at the end of the article © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creativecommons.org/licenses/by/4.0/](http://creativecom

FAQs

How does loss of IRF2 affect MHC I pathway activity in tumors?

Transcriptomic analyses show reduced IRF2 expression is accompanied by decreased transcription of IRF2-regulated MHC I pathway genes needed for CD8 T cell recognition. Gene-edited melanomas further confirm reduced MHC I pathway transcripts and lower MHC I complex levels on the cell surface.

What is the impact of IRF2 loss on checkpoint immunotherapy response?

IRF2 loss makes both human and mouse melanomas resistant to checkpoint inhibitor immunotherapy. The resistance is linked to impaired antigen presentation through diminished MHC I pathway function.

Can the effects of IRF2 loss be reversed?

Yes. Interferon stimulation of IRF2-deficient melanomas induces IRF1, a functionally homologous transcription factor, which restores the MHC I pathway and responsiveness to checkpoint blockade immunotherapy.

Sep 21, 2026

Uploaded by Riley