# Project 1: Inhibition of Complement C5aR1 Radioprotects Normal Tissue and Radiosensitizes Tumors

> **NIH NIH P01** · STANFORD UNIVERSITY · 2022 · $259,314

## Abstract

Abstract (Project 1 - Oxford)
Increasing the therapeutic window of radiotherapy may be achieved by using targeted therapies against cancer-
associated pathways. The complement system is an innate immunity pathway, with emerging roles in cancer
progression. No study has evaluated the effect of complement inhibition on both tumor and normal tissue
radiation response. Here we show that targeting complement receptor C5aR1 improves radiation response in
colorectal cancer models while reducing radiation-induced toxicity. Targeting C5aR1 increases IL-10 secretion,
which attenuates NF-κB signaling and enhances apoptosis in tumor cells. IL-10-dependent apoptosis is
observed both in vivo and in vitro suggesting a non-canonical stress-specific and likely immune-independent role
for C5aR1 in regulating apoptosis. Importantly, we find that C5aR1 depletion results in decreased small intestinal
histologic damage, crypt cell apoptosis and increased survival of mice following irradiation. In the small intestine,
C5aR1 depletion results in increased IL-10 expression in both non-immune and immune cell populations. IL-10
signaling in CX3CR1+ macrophages is important for intestinal injury defense and C5aR1-/- mice have significantly
higher levels of CX3CR1+ macrophages than WT mice. In response to irradiation, C5aR1 depletion does not
attenuate NF-κB signaling but instead increases AKT activation correlating with decreased apoptosis occurring
in an IL-10-depedent manner. Our data, therefore, indicate that genetically or pharmacologically targeting C5aR1
can improve radiation response in colorectal tumor models while reducing radiation-induced small bowel toxicity.
Together, these findings suggest that inhibiting complement could be a promising approach to increasing the
therapeutic window of radiotherapy. In this Project, we propose four specific aims to better understand the role
of C5aR1 in radioprotection and radiosensitization. Aim 1 will determine the broad versus specific protection of
normal epithelium (intestines, salivary glands, and lung epithelium) by C5aR1-/- mice in response fractionated
and hypofractionated radiotherapy, in collaboration with Projects 2, 3, 4 and Core B. In Aim 2, we will investigate
the mechanistic basis of radioprotection when C5aR1 is inhibited. Our preliminary data indicates that this is an
IL-10 dependent mechanism and involves recruitment of CX3CR1+ macrophages that promote survival and
angiogenesis. Aim 3 will determine how C5aR1 promotes tumor cell killing in combination with radiotherapy.
The hypothesis based on our preliminary data is that C5aR1 inhibition increases IL-10 secretion, which
attenuates NF-κB signaling, resulting in IL-10 dependent tumor cell killing both in cell culture and in animal
models. Aim 4 will determine the effect of clinical grade C5aR1 inhibitors on radioprotecting intestine, salivary
glands and lungs, and sensitizing colorectal tumors to radiotherapy. I intend to return to Stanford on a monthly
or bim...

## Key facts

- **NIH application ID:** 10334199
- **Project number:** 1P01CA257907-01A1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Amato J. Giaccia
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $259,314
- **Award type:** 1
- **Project period:** 2022-09-21 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10334199

## Citation

> US National Institutes of Health, RePORTER application 10334199, Project 1: Inhibition of Complement C5aR1 Radioprotects Normal Tissue and Radiosensitizes Tumors (1P01CA257907-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10334199. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*