# Triggering Aberrant RNA Processing for RCC Therapy

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $618,057

## Abstract

ABSTRACT
 Renal cell carcinoma (RCC) is one of the most lethal urologic malignancies with approximately 81,800
new cases and 15,000 deaths estimated in 2023. Clear cell RCC (ccRCC) along with melanoma has
traditionally been viewed as an immunotherapy responsive disease with a storied history of immunotherapy
treatments including high dose interleukin 2 (IL2), interferon, and allogeneic stem cell transplant. Indeed, RCC
was one of the first tumor types to garner FDA approval for PD1 immune checkpoint inhibition (ICI). However,
unlike melanoma, most RCC tumors do not have a high tumor mutational burden (TMB) to potentially explain
their immunotherapy responsiveness. We and others have sought to explain this unanswered question and
have demonstrated that non-canonical tumor associated antigens like endogenous retroviruses (ERVs) may in
part explain ICI response in RCC. Nonetheless, ERV expression is unlikely to fully explain ccRCC ICI response
and only 25% of RCC patients respond to single-agent ICI. Therefore, further enhancing ICI response will be
clinically meaningful.
 A collaboration between the Kim and Dominguez labs has uncovered another potentially robust source
of tumor associated antigens - retained introns. We have noted that ccRCC tumors have the highest level of
retained introns (RI) across all TCGA tumors, that RI levels are secondary to suppressed non-sense mediated
decay (NMD) activity, and that one can subset ccRCC into RI-high and normal-like tumors. Moreover, we have
found that mTOR signaling plays a key role in regulating NMD and intron retention and that mTOR inhibition
can promote intron retention. Finally, our preliminary data demonstrates, in a clinical dataset, that ICI
responsive tumors are enriched in a RI-high phenotype. In this proposal we will assess how NMD is regulated
in ccRCC (Aim 1), determine the impact of suppressed NMD on ccRCC tumorigenicity (Aim 2), and determine
the impact of NMD suppression and resultant enhanced intron retention on the tumor immune
microenvironment and ICI response (Aim 3). Successful completion of our proposal will establish sound
scientific premise for combining two FDA approved RCC therapies (mTOR inhibition and ICI) to promote
expression of highly foreign neoantigens from retained introns (neo-RI-antigens), which should provoke a
robust, antigen-driven immune response that can be leveraged to enhance immune checkpoint blockade.

## Key facts

- **NIH application ID:** 10872897
- **Project number:** 1R01CA290597-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Daniel Issac Dominguez
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $618,057
- **Award type:** 1
- **Project period:** 2024-03-12 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10872897

## Citation

> US National Institutes of Health, RePORTER application 10872897, Triggering Aberrant RNA Processing for RCC Therapy (1R01CA290597-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10872897. Licensed CC0.

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