Abstract P016: Optimizing macrophage-mediated abscopal effects for enhanced clinical translation: Radiation therapy combined with CD47 blockade
Authors: Nishiga Yoko , Graves Edward , Sage Julien 
Published: January 2025

Abstract
Radiation therapy (RT) can activate both innate and adaptive immune responses, and the combination of RT and immunotherapy may produce synergistic anti-tumor responses. We found that the “don’t-eat-me” molecule CD47 is highly expressed on the surface of small cell lung cancer (SCLC) cells, a highly metastatic form of lung cancer, and that blockade of CD47 can enhance phagocytosis of SCLC cells by macrophages. In this study, we investigated whether combining CD47 blockade and RT could synergize to inhibit the tumor growth of SCLC as well as other cancer types in preclinical models. We evaluated the immune responses induced by RT and CD47 blockade and their efficacy in controlling tumors in preclinical models of SCLC as well as colon cancer, breast cancer and lymphoma. Cancer cells were engrafted into both flanks of recipient mice and one side was irradiated, with or without CD47 antibodies, to investigate local and systemic effects of RT and CD47 blockade. We also used liver metastases models and endogenous lung tumor models to investigate anti-tumor effects and immune responses in physiological tumor microenvironments. Various radiation doses and fractionation schedules were evaluated to determine the optimal conditions for inducing anti-tumor responses. We found CD47 blockade potently enhances the local anti-tumor effects of RT in all the preclinical models of SCLC we tested. Strikingly, CD47 blockade also stimulates systemic “abscopal” effects inhibiting non-irradiated SCLC tumors in mice receiving RT. These effects are observed in liver metastases, endogenous lung tumors, and subcutaneous tumor models. Surprisingly, these abscopal effects are independent of T cells but require macrophages that migrate into non-irradiated tumor sites in response to inflammatory signals produced by RT and are locally activated by CD47 blockade to phagocytose cancer cells. Similar abscopal anti-tumor effects were observed in other cancer models treated with RT and CD47 blockade. Additionally, we observed that RT increases tumor infiltrating macrophages in human cancer patients. Interestingly, these abscopal anti-tumor effects can be enhanced when combined with PD-1 blockade. Furthermore, we found that a wide range of radiation doses, from 2 Gy to 20 Gy, can induce abscopal responses, with fractionated doses (24 Gy in 3 fractions) inducing stronger abscopal effects than single doses. Our data demonstrate macrophage-mediated abscopal responses following RT when combined with CD47 blockade across multiple cancer models. This systemic activation of anti-tumor macrophages following RT and CD47 blockade may be particularly impactful for cancer patients who suffer from metastatic disease. Given that RT is a standard-of-care treatment and CD47-blocking strategies are undergoing clinical trials, our findings hold significant translational potential for cancer patients.
Citation Format: Yoko Nishiga, Edward Graves, Julien Sage.Optimizing macrophage-mediated abscopal effects for enhanced clinical translation: Radiation therapy combined with CD47 blockade.[abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr P016