# Elucidating the Roles of RNA m6A readers Y1 and Y2 in radiation-induced immunity and immunotherapy

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2021 · $412,712

## Abstract

Project Summary
Cancer is a leading cause of death worldwide. Recent advancements in the use of immune checkpoint
blockade have transformed oncology, and immunotherapy has extended the potential application of
radiotherapy to systemic disease. More than 200 clinical trials of combined checkpoint blockade and
radiotherapy are ongoing or completed. The results of these preliminary trials demonstrate efficacy only in a
limited subpopulation of patients. Treatment resistance likely manifested by poor T-cell priming and tumor-
mediated immunosuppression continue to constitute significant barriers to optimal patient outcomes; therefore,
the opportunity for transformative clinical impact is real in this setting.
 We propose a new and innovative strategy guided by new findings to improve the interaction of
radiotherapy and immunotherapy by incorporating the latest techniques in the emerging field of mRNA
modification with well-established radiobiological and immunological approaches. We will leverage
collaboration with our Co-Investigator Chuan He, who helped to discover and decipher reversible RNA
methylation in post-transcriptional gene expression regulation. We will use the novel techniques to identify the
binding sites of Y1 and Y2, and incorporate integrated bioinformatics analysis approaches to investigate the
impact of m6A readers in functional pathways of immune cells in irradiated tumors. These techniques are new
and, to our knowledge, have yet to be applied in the context of radiotherapy and radioimmunotherapy.
 We hypothesize that targeting regulation of m6A modifications associated with m6A-binding protein
YTHDF1 (for improved antigen presentation and T-cell priming) and YTHDF2 (for alleviation of
immunosuppression) will potentiate anti-tumor immunity in the context of both RT alone and RT combined with
anti-PD-L1 antibodies. Our proposal focuses on 1) establishing YTHDF1 (Aim 1) and YTHDF2 (Aim 2) as
viable targets for RT and radioimmunotherapy, and 2) uncovering underlying pathways. Small molecules from
the He Lab will be used to validate our hypothesis. The ultimate goal of this therapeutic approach is to
modulate gene expression via targeting m6A methylation related to translation (Y1) or degradation (Y2) of
mRNA in order to potentiate immune response.
 We are uniquely positioned to discover new knowledge and elucidate an unprecedented level of
mechanistic understanding of the complex molecular and cellular interplay between radiotherapy and
checkpoint inhibition in the context of the immune system. These new findings will provide the mechanistic
data required for translational pursuit of superior treatment strategies. Increased local and/or distant control to
actualize radio-immunotherapy would be a practice-changing and would broadly enhance cancer care and
expand the pool of patients who respond to inhibition of the PD-1/PD-L1 axis.

## Key facts

- **NIH application ID:** 10279950
- **Project number:** 1R01CA262508-01
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** RALPH R WEICHSELBAUM
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $412,712
- **Award type:** 1
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10279950

## Citation

> US National Institutes of Health, RePORTER application 10279950, Elucidating the Roles of RNA m6A readers Y1 and Y2 in radiation-induced immunity and immunotherapy (1R01CA262508-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10279950. Licensed CC0.

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