# Expanding the tumor antigen landscape and maintaining APCs in a T cell-activating state to restore tumor immunity

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2024 · $449,997

## Abstract

The goals of this study are to understand how inhibiting DNA-PK activity 1) induces and increases tumor
antigen/neoantigen expression in weakly immunogenic tumors and 2) contributes to maintaining dendritic cells
and myeloid cells in a T cell-activating state. These goals are motivated by exciting clinical results which
demonstrate that T cell-based immunotherapies can mediate tumor regression but also because durable
responses to current therapies are observed in only a subset of patients and against a limited number of
cancers. Favorable responses to immunotherapies correlate with levels of neoantigens and changes in the
tumor-reactive TCR repertory. Cancers can evade T cell detection by downregulating major histocompatibility
complex (MHC I) and antigen expression. We screened ~2,500 compounds for the ability to selectively
regulate the expression of various tumor-associated antigens (TAAs) and increase MHC I expression. Among
the most effective drugs were DNA-PK inhibitors. Our preliminary studies indicate that DNA-PK inhibition
increases and diversifies the expression of various TAAs and neoantigens in melanoma at the transcriptional
level leading to increased protein expression. Further, reduced DNA-PK levels or DNA-PK mutations in patient
samples are associated with increased tumor infiltrating lymphocytes (TIL) and tumor mutation burden. The
overarching hypothesis is that DNA-PK plays a novel role as a transcriptional regulator that modifies the
expression of melanoma tumor antigens, including neoantigens, and thereby increases the diversity,
frequency, and activity of tumor-reactive T cells. We further postulate that inhibiting DNA-PK activity in DCs
and myeloid cells reduces their propensity to enter a T cell-suppressive state. These hypotheses will be
addressed through the following aims. In Aim 1, we will determine the molecular mechanisms by which DNA-
PKcs regulates tumor antigen expression by determining the role of kinase activity, identifying the DNA-PK
substrate(s) that contribute to its repressive function, and to define the roles that the individual DNA-PK
subunits play in transcriptional regulation. Aim 2 will ascertain the in vivo impact that DNA-PK inhibition has on
increasing and diversifying the tumor-reactive T cell repertoire. We seek to demonstrate that DNA-PK inhibition
treatment increases the number and activity of neoantigen-reactive T cells. Aim 3 will determine the impact
that inhibiting DNA-PK has on inducing and sustaining stimulatory signals on tumor derived dendritic and
myeloid cells. We will determine how DNA-PK inhibition prevents DCs and myeloid cells from a entering a T
cell-suppressive state. The proposed studies are significant as they will offer molecular and cellular insights as
to how DNA-PK activity contributes to tumor immunogenicity and exploit these insights to develop more
reliable biomarkers and effective therapies against weakly immunogenic tumors.

## Key facts

- **NIH application ID:** 10836455
- **Project number:** 5R01CA271537-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Eduardo V Davila
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $449,997
- **Award type:** 5
- **Project period:** 2023-05-03 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10836455

## Citation

> US National Institutes of Health, RePORTER application 10836455, Expanding the tumor antigen landscape and maintaining APCs in a T cell-activating state to restore tumor immunity (5R01CA271537-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10836455. Licensed CC0.

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