# The Impact of ATR Kinase Inhibitors on CD8+ T Cell Expansion and Memory Development

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $69,960

## Abstract

PARENT GRANT – ABSTRACT (as per original submission)
The overarching goal of our laboratory is to determine how DNA damage response inhibitors (DDRi) can be used
to potentiate cancer cell killing while concurrently increasing anti-tumor immune responses after radiation therapy
(XRT). The DNA Damage Response (DDR) is a signaling system that integrates DNA repair pathways and the
cell cycle to safeguard genome stability. In addition to activating cell cycle checkpoints and DNA repair in cells
treated with XRT, the DDR limits origin firing and delays cell cycle transitions in unstressed cells. While cyclin-
dependent kinases are cell cycle accelerators, DDR kinases are cell cycle brakes and, in this analogy, DDRi
disable the brakes, causing unchecked acceleration. Here we will determine how the DDR is rewired in CD8+ T
cells to accommodate massive and concomitant DNA replication and transcription in S phase. We will also
determine the impact of DDRi in cancer and immune cells. We hypothesize that ATR kinase inhibitors induce
origin firing that causes ribonucleosides to be mis-incorporated into the genome, and that this generates
chimeric RNA-DNA fragments and type I IFN-dependent immunologic memory after XRT. To test our
hypothesis in cancer and immune cells, we have generated an innovative transplantable model of cancer. The
Mcm4Chaos3/Chaos3 mouse carries a mutation in Mcm4 that destabilizes the replicative helicase. Cells derived
from Mcm4Chaos3/Chaos3 mice have a 60% reduction in origin licensing. We have generated
Mcm4Chaos3/Chaos3 B16 cancer cells that can be transplanted into Mcm4wt/wt and Mcm4Chaos3/Chaos3
mice. This will allow us to separate the function of ATR that limits origin firing from that which mediates the repair
of replication forks in cancer and immune cells. In Aim 1, we will define cell cycle kinetics and determine how
ATR inhibitors induce DNA damage in immune and cancer cells in vitro. In Aim 2, we will define cell cycle kinetics
and determine whether ATR inhibitors induce DNA damage in immune cells and type 1 interferons in vivo. In Aim
3, we will determine whether ATR inhibitors combine with XRT to generate durable responses and immunologic
memory through effects on immune and/or cancer cells. Successful completion of this project will define how the
DDR is rewired in CD8+ T cells to accelerate cell cycle transitions and accommodate massive and concomitant
DNA replication and transcription in S phase which, accounts for ~70% of the cell cycle as G1 is abridged. These
studies are highly significant as the objective of checkpoint blockade and adoptive T cell transfer is to induce
rapid division in CD8+ T cells. Successful completion of this project will identify combinations and sequences of
DDRi that potentiate cancer cell killing while concurrently increasing anti-tumor immune responses in mouse
models of cancer treated with XRT. These studies are highly significant as we use DDRi that are currently in 115
clinical trials a...

## Key facts

- **NIH application ID:** 11061551
- **Project number:** 3R01CA266172-03S1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** CHRISTOPHER J. BAKKENIST
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $69,960
- **Award type:** 3
- **Project period:** 2022-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11061551

## Citation

> US National Institutes of Health, RePORTER application 11061551, The Impact of ATR Kinase Inhibitors on CD8+ T Cell Expansion and Memory Development (3R01CA266172-03S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11061551. Licensed CC0.

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