# DNA damage signaling to immune checkpoints

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $358,311

## Abstract

Lung cancer is diagnosed late, has a 5 year survival of only 15%, and kills more people than colorectal,
breast and prostate cancer combined. Less than 30% of lung cancers are resected and the majority of
patients are treated with cisplatin and ionizing radiation (IR). We show that inhibition of DNA damage signaling
by ATR kinase during treatment with cisplatin and IR is well-tolerated and leads to durable responses in mouse
xenograft and genetic models of lung cancer. Quite unexpectedly, we show that in addition to potentiating
DNA damage, two clinical ATR kinase inhibitors (ATRi’s), with unrelated structures, block expression of the
immune checkpoint protein PD-L1 and increase presentation of MHC class I antigens in lung cancer cells after
IR. Our finding that crosstalk exists between DNA damage signaling and immune checkpoints has not been
described previously and is the focus of this proposal. Immune-inhibitory pathways, termed immune
checkpoints, are coopted by tumor cells to evade cytotoxic immune cells. PD-1 is expressed on cytotoxic T
cells and its ligand PD-L1 is upregulated in lung cancers. PD-L1 binding by PD-1 prevents the activation of
cytotoxic T cells. Immune checkpoint blockade using anti-PD-L1 and anti-PD-1 antibodies restores anti-tumor
immune responses and is emerging as an exciting lung cancer therapy. We propose that ATRi’s inhibit DNA
repair and cell cycle checkpoints potentiating the DNA damage induced by cisplatin and IR while concurrently
inhibiting PD-L1 expression and restoring anti-tumor immune responses. Our objective in this proposal is to
define the mechanisms that connect DNA damage signaling and immune checkpoints. This objective will be
accomplished by the following Specific Aims. Aim 1: To determine how ATRi’s inhibit PD-L1 expression in lung
cancer cells after IR. This aim will define the contribution of ATR, ATM, IRF-1, NF-κB and p53 to PD-L1
expression after IR. Aim 2: To determine how ATRi’s increase MHC class I expression on lung cancer cells
after IR. This aim will identify ATR, ATM, and p53 signaling that inhibits protein synthesis and MHC class I
presentation after IR. Aim 3: To identify ATRi-induced PDL-1/PD-1 immune checkpoint blockade in lung cancer
after IR. This aim will identify ATRi-induced immune checkpoint blockade in lung cancer after IR. The
outcomes of these Aims will identify mechanisms that connect DNA damage signaling to immune self-
tolerance. This will define a novel therapeutic opportunity to use ATRi’s to potentiate the DNA damage
induced by cisplatin and IR while concurrently inducing immune checkpoint blockade.

## Key facts

- **NIH application ID:** 9843645
- **Project number:** 5R01CA204173-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** CHRISTOPHER J. BAKKENIST
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $358,311
- **Award type:** 5
- **Project period:** 2017-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9843645

## Citation

> US National Institutes of Health, RePORTER application 9843645, DNA damage signaling to immune checkpoints (5R01CA204173-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9843645. Licensed CC0.

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