# Targeting the DNA damage response in combination with radiation to induce innate immunity and improve immunotherapy efficacy in pancreatic cancer

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $452,277

## Abstract

ABSTRACT
Therapeutic strategies are needed to improve the efficacy of immune checkpoint blockade (ICB) therapy in
pancreatic ductal adenocarcinomas (PDAC). PDACs have an increased reliance on the DNA damage response
(DDR) for mitigating oncogene-induced replication stress and, the DDR regulates innate immunity via regulation
of cGAS/STING/TBK1-mediated detection of cancer DNA. ATM is the apical kinase in the DDR and the target
of small molecule inhibitors in clinical development. Furthermore, ionizing radiation stimulates the
cGAS/STING/TBK1 innate immune pathway to modulate immune responses in a type 1 interferon (T1IFN)-
dependent fashion that are required for the synergy of radiation with ICB. Therefore, the central hypothesis
of this proposal is that a novel direct link between ATM and innate immune sensing pathways can be
leveraged therapeutically in combination with radiation to enhance the tumoral T1IFN pathway and
improve ICB efficacy in otherwise poorly immunogenic PDACs. This hypothesis will be tested in three
specific aims: Aim 1 will define the immunologic consequences of ATM inhibition in combination with
radiation and the mechanisms by which ATM affects innate immunity in PDAC. In this aim we will assess
the contributions of cytoplasmic DNA (1A), ATM substrates (1B), and pattern recognition receptor pathway
signaling (1C) to immune endpoints such as T1IFN-mediated signaling, PD-L1 expression, and T cell-mediated
killing (1D). Aim 2 will investigate the immune contribution to the sensitivity of ATM depleted PDAC
tumors to the combination of radiation and PD-L1 therapy. Our preliminary data suggest that ATM has both
tumor and host immune-dependent mechanisms (i.e. T1IFN secretion) that influence the sensitivity of tumors to
combined anti-PD-L1 and radiation. We will determine the contribution of tumoral and host T1IFN signaling to
the sensitivity of ATM-deficient tumors to combined anti-PD-L1 and radiation therapy (2A) as well as the immune
consequences (2B). We hypothesize that the therapeutic advantages of ATM deficiency will be diminished in
T1IFNR deficient tumor cells and hosts since tumoral T1IFN production likely increases tumor
immunosurveillance through both tumor and host-dependent mechanisms. In Aim 3 we will develop a
therapeutic strategy combining ATM inhibitors and radiation with anti-PD-L1 in PDAC. Our preliminary
data show that pharmacologic ATM inhibition activates the immune pathway. We will determine the efficacy of
the clinical candidate ATM inhibitor AZD0156 in combination with anti-PD-L1 and the optimal radiation
dose/fractionation schema in syngeneic PDAC tumors and autochthonous PDAC tumors in genetically
engineered mouse models (3A). We will also develop pharmacodynamic biomarkers that will be predictive of the
therapeutic efficacy of ATM inhibition and radiation in combination with anti-PD-L1 (3B). Completion of these
aims will define a new connection between ATM, radiation and innate immunity that will be le...

## Key facts

- **NIH application ID:** 10112209
- **Project number:** 5R01CA240515-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Meredith A Morgan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $452,277
- **Award type:** 5
- **Project period:** 2020-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10112209

## Citation

> US National Institutes of Health, RePORTER application 10112209, Targeting the DNA damage response in combination with radiation to induce innate immunity and improve immunotherapy efficacy in pancreatic cancer (5R01CA240515-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10112209. Licensed CC0.

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