# Role of IRF2 in cancer immune evasion and immunotherapy

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2020 · $582,872

## Abstract

Abstract
CD8 T lymphocytes are the major mechanism by which the immune system eliminates cancers and virally
infected cells. CD8 T cells detect these abnormal targets by recognizing immunogenic (e.g. viral or mutant)
peptides displayed on MHC I molecules. Cancers and viruses can evade immune control and elimination by
inhibiting MHC I antigen presentation, making them harder to detect, and/or by expressing molecules, such as
PDL1, that inhibit attacking T cells. Therefore, it is important to understand the mechanisms by which tumors
dysregulate these processes, how this affects cancer progression and immunotherapy, and how to reverse the
immune evasion to improve outcomes - these are the overall goals of this proposal. Our proposal is based on
our discovery in an unbiased forward genetic screen, of a transcription factor, IRF2, that unexpectedly is a
positive regulator of MHC I antigen presentation and a negative regulator of PDL1 (CD274) expression. Our
first aim will test the hypotheses that loss of expression of IRF2 is one of the ways that cancers escape
immune surveillance and control to progress and that this is associated with worse clinical outcomes. Our
second aim will test the hypotheses that the loss of IRF2 impairs the success of immunotherapy and that IRF2
will provide a much-needed biomarker to identify patients who would benefit, or not, from immunotherapy. The
rational for this hypothesis is that the reduction in MHC I antigen presentation caused by loss of IRF2, will
impair the ability of CD8 T cell responses that are invigorated by checkpoint blockade to find and kill their
cancer targets. Our third aim hypothesizes that the loss of IRF2 expression is due to epigenetic silencing. Our
goal is to determine the underlying mechanism for loss of IRF2 expression and to develop approaches to
reverse the immune evasion caused by the loss of IRF2 that can be translated into future clinical trials. Our
experimental approaches will use IRF2 gain of function and loss of function models, together with humanized
and IRF2 KO mice to define the role of IRF2 in tumor immune evasion and responsiveness to immunotherapy
with checkpoint blockade for both human and mouse cancers (Melanoma, NSCLC, & MCA sarcomas). We will
translate these findings into human cancer patients, evaluating whether IRF2 is a biomarker that can predict
clinical course and/or responsiveness to immunotherapy. Support for our hypotheses and feasibility of the
proposed experiments are supported by strong preliminary data. Finally, we will use bioinformatics, seq
techniques, inhibitors and cytokines to elucidate how IRF2 expression is lost and how to circumvent this loss
for therapy.

## Key facts

- **NIH application ID:** 10051750
- **Project number:** 1R01CA247624-01A1
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** KENNETH L ROCK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $582,872
- **Award type:** 1
- **Project period:** 2020-06-29 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10051750

## Citation

> US National Institutes of Health, RePORTER application 10051750, Role of IRF2 in cancer immune evasion and immunotherapy (1R01CA247624-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10051750. Licensed CC0.

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