CD47 in the Tumor Microenvironment Limits Cooperation between Antitumor T-cell Immunity and Radiotherapy

Abstract

While significant advances in radiotherapy have increased its effectiveness in many cancer settings, general strategies to widen the therapeutic window between normal tissue toxicity and malignant tumor destruction would still offer great value. CD47 blockade has been found to confer radioprotection to normal tissues while enhancing tumor radiosensitivity. Here we report that CD47 blockade directly enhances tumor immunosurveillance by CD8+ T cells. Combining CD47 blockade with irradiation did not affect fibrosarcoma growth in T cell-deficient mice, whereas adoptive transfer of tumor-specific CD8+ T cells restored combinatorial efficacy. Further, ablation of CD8+ T cells abolished radiotherapeutic response in immunocompetent syngeneic hosts. CD47 blockade in either target cells or effector cells was sufficient to enhance antigen-dependent CD8+ CTL-mediated tumor cell killing in vitro. In CD47-deficient syngeneic hosts, engrafted B16 melanomas were 50% more sensitive to irradiation, establishing that CD47 expression in the microenvironment was sufficient to limit tumor radiosensitivity. Mechanistic investigations revealed increased tumor infiltration by cytotoxic CD8+ T cells in a CD47-deficient microenvironment, with an associated increase in T cell-dependent intratumoral expression of granzyme B. Correspondingly, an inverse correlation between CD8+ T cell infiltration and CD47 expression was observed in human melanomas. Our findings establish that blocking CD47 in the context of radiotherapy enhances antitumor immunity by directly stimulating CD8+ cytotoxic T cells, with the potential to increase curative responses.

Targeting CD47 and Autophagy Elicited Enhanced Antitumor Effects in Non–Small Cell Lung Cancer

“…Meanwhile, new data from the phase I trial of TTI-621 (a SIRPaFc fusion protein) suggest that repeat dosing of TTI-621 overcame the antigen sink while maintaining clinically acceptable platelet levels (33), which could be an effective strategy to circumvent antigenic sinks in other studies. Although many studies have revealed that the therapeutic benefit of blocking CD47-SIRPa interactions in immune competent hosts depends on the myeloid immune subsets, including neutrophils, NK cells, T cells, and dendritic cells (34)(35)(36), the primary cell type contributing to effectiveness is macrophages (10,(37)(38)(39). Our data here also showed that targeting CD47 by SIRPaD1-Fc elicited potent macrophage-mediated antitumor efficacy in NSCLC.…”

Anti-SIRPα antibodies as a potential new tool for cancer immunotherapy

“…Moreover, depletion of either of these cell types resulted in marked attenuation of the antitumor effect of MY-1, implicating these immune cells in this effect. It has recently been demonstrated that the efficacy of CD47 blockage against tumors required adaptive immune responses in immunocompetent mouse tumor models (48)(49)(50). The inhibition of the CD47-SIRPα interaction by SIRPα or CD47 blockage is thus probably important for enhancing T cell-mediated destruction of tumors.…”

CD47 Receptor Globally Regulates Metabolic Pathways That Control Resistance to Ionizing Radiation

“…The radioresistance of cd47-null cells or blockade of CD47 in WT cells requires induction of protective autophagy (22). Moreover, studies in tumor-bearing mice revealed that, although normal tissues and tumor associated CD8 ϩ T cells in these mice are protected from radiation injury, irradiated tumors show increased CD8 ϩ T cell-dependent therapeutic ablation after CD47 blockade (20,23). Thus, the CD47 pathway is a promising therapeutic target to enhance the efficacy of tumor irradiation while minimizing damage of critical organs exposed to the radiation field.…”