# (PQ11) Targeting STING in the context of chemoradiation therapy to overcome poor preexisting immunity in mouse models of pancreatic cancer.

> **NIH NIH R01** · PROVIDENCE PORTLAND MEDICAL CENTER · 2020 · $377,438

## Abstract

Project Summary
Nearly two-thirds of all cancer patients will receive radiation therapy (RT) during treatment, but radiation's
curative potential is limited to local-regional disease in either the definitive or adjuvant setting. Locally
advanced, unresectable disease represents 30-40% of pancreatic cancer patients at diagnosis and carries a 5-
year survival rate of less than 1%. While RT is frequently used and highly effective in metastatic cancer for
palliation of symptomatic disease, it has little impact on unirradiated distant sites and thus no impact on
survival in the metastatic setting. Likewise in the setting of locally advanced regional disease, such as in
pancreatic cancer, radiation is frequently studied in the neoadjuvant setting but with little apparent
improvement in overall survival. We have found that radiation therapy activates a myeloid response in the
tumor that suppresses adaptive immunity. By targeting the STING (STimulator of INterferon Genes) sensor
with cyclic dinucleotides (CDN), we have found that we can prevent suppressive myeloid responses, and when
CDN are combined with radiation therapy we can control aggressive murine tumors. We hypothesize that
provision of STING ligands in combination with chemoradiation therapy removes the biomarkers of poor
response to immunotherapy. We propose that ligation of STING in systemic monocytes that are recruited to
tumors following radiation and/or chemotherapy prevents transition to a tumor-promoting environment and
enhances tumor associated T cell responses. The specific aims of this study are to 1: Test the hypothesis
that the multicomponent chemoradiation therapy for pancreatic cancer contains core components critical to
generate adaptive tumor-specific immune response when combined with systemic STING ligand treatment; 2:
Test the hypothesis that the enhanced tumor control provided by systemic STING ligand in combination with
radiation therapy and/or chemotherapy results from recruitment of repolarized monocytes to the tumor that in
turn promote adaptive immunity in the post-treatment tumor environment; 3: Test the hypothesis that
immunotherapies targeting the myeloid compartment via STING ligands will be required for tumors with the
biomarkers of poor preexisting immunity and high myeloid involvement. Our study design incorporates
preclinical chemoradiation therapy of transplantable and spontaneous models of pancreatic cancer in immune
competent mice using an advanced imaging and treatment platform. This proposal particularly focuses on
control of both local-regional and distant disease to extend the curative potential of immunotherapy for cancer
patients.

## Key facts

- **NIH application ID:** 10000071
- **Project number:** 5R01CA208644-05
- **Recipient organization:** PROVIDENCE PORTLAND MEDICAL CENTER
- **Principal Investigator:** Marka Crittenden
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $377,438
- **Award type:** 5
- **Project period:** 2016-09-02 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10000071

## Citation

> US National Institutes of Health, RePORTER application 10000071, (PQ11) Targeting STING in the context of chemoradiation therapy to overcome poor preexisting immunity in mouse models of pancreatic cancer. (5R01CA208644-05). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10000071. Licensed CC0.

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