# Radiation therapy eliminating cancer by SIRPa depletion

> **NIH NIH R21** · GEORGIA STATE UNIVERSITY · 2020 · $169,016

## Abstract

Abstract
Radiation therapy (RT) is a major treatment modality for various forms of cancers including solid tumors and
metastases. Recent advances found that the efficacy of RT, particularly for achieving curative and abscopal
effects, is heavily dependent on the induction of anti-tumor T cell immunity, especially the tumoricidal activity of
CD8 T cells. Despite that various strategies comprising fractionated radiation and/or combinatorial immune
modulators have been explored to enhance the CD8 T cell activity in RT, preclinical studies and clinical trials
thus far have attained suboptimal results, especially when tumors are well-established, large or are poorly
immunogenic. In our preliminary studies, we tested whether depletion of SIRPα, a negative regulator of
phagocytic leukocytes, would improve RT efficacy. The results were stunning; a single fraction of low-dose
radiation (8Gy or 20Gy), which had no effect on tumor-burdened WT mice, led to complete responses and
eliminated all traces of MC38 and Pan02 carcinoma tumors in Sirpα-/- mice – not only smaller tumors (< 200mm3)
but also those of large sizes (> 400mm3). With this combinatorial strategy, we observed greatly enhanced CD8
T cell tumoricidal activities attributable to 1) successful early-stage Sirpα-/- phagocytes/APCs uptake and
presentation of tumor antigens and subsequent tumor-specific T cell activation and tumor infiltration, and 2)
marked reduction of immunosuppressive components, including Tregs, MDSCs and tumor expression of PD-L1,
in the tumor microenvironment (TME) following RT. The RT-induced anti-tumor adaptive immunity in SIRPα-/-
mice was further exhibited by abscopal effects that cleared distal tumors, resistance to future tumor engraftments
and in recipient WT mice to which tumor-specific CD8 T cells were adoptively transferred. These preliminary
results are profound, leading to the postulation that SIRPα interaction and signaling prominently inhibit the RT-
induced immune response toward cancer and that SIRPα deficiency provides a new foundation for developing
highly efficacious anti-tumor RT modalities. Our central hypothesis is that SIRPα deficiency steers RT to
robustly activate tumor antigen presentation to lymphocytes and alter the TME to become non-tolerogenic,
leading to enhanced T cell tumoricidal activity and long-lasting adaptive immunity. We will test this hypothesis
by two aims: Aim 1 is to determine how depletion of SIRPα allows RT-activated APCs to robustly activate tumor-
specific CD8 T cells and how this is suppressed by SIRPα signaling; Aim 2 is to determine the mechanism(s) by
which RT induces an anti-tumor, non-tolerogenic TME in Sirpα-/- mice. Clearly, these studies point to extremely
important knowledge and unprecedented cancer immunotherapy mechanisms, application of which will bring
about revolutionary breakthrough in RT modalities for cancer eradication, as well as producing long-lasting
effective adaptive immunity that exhibits abscopal effects a...

## Key facts

- **NIH application ID:** 9936134
- **Project number:** 5R21CA241271-02
- **Recipient organization:** GEORGIA STATE UNIVERSITY
- **Principal Investigator:** YUAN LIU
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $169,016
- **Award type:** 5
- **Project period:** 2019-06-01 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9936134

## Citation

> US National Institutes of Health, RePORTER application 9936134, Radiation therapy eliminating cancer by SIRPa depletion (5R21CA241271-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9936134. Licensed CC0.

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