CD47 blockade enhances the efficacy of intratumoral STING-targeting therapy by activating phagocytes

Abstract

Activation of STING signaling plays an important role in anti-tumor immunity, and we previously reported the anti-tumor effects of STING through accumulation of M1-like macrophages in tumor tissue treated with a STING agonist. However, myeloid cells express SIRPα, an inhibitory receptor for phagocytosis, and its receptor, CD47, is overexpressed in various cancer types. Based on our findings that breast cancer patients with highly expressed CD47 have poor survival, we evaluated the therapeutic efficacy and underlying mechanisms of combination therapy with the STING ligand cGAMP and an antagonistic anti-CD47 mAb using E0771 mouse breast cancer cells. Anti-CD47 mAb monotherapy did not suppress tumor growth in our setting, whereas cGAMP and anti-CD47 mAb combination therapy inhibited tumor growth. The combination therapy enhanced phagocytosis of tumor cells and induced systemic anti-tumor immune responses, which rely on STING and type I IFN signaling. Taken together, our findings indicate that coadministration of cGAMP and an antagonistic anti-CD47 mAb may be promising for effective cancer immunotherapy.

Pro-Resolving Factor Administration Limits Cancer Progression by Enhancing Immune Response Against Cancer Cells

“…TAM controlled circulating cancer cell recruitment to the primary tumors and are involved in the metastatic cascade ( 29 , 53 , 55 , 57 , 58 ). Several studies have shown that targeting macrophages improved cancer outcome, either by depleting them with clodronate liposome injection for instance, blocking the phagocytosis pathway, inhibiting their recruitment (CXCR2/CCL2 pathway blocking), targeting CD47, or by reprogramming them toward an anti-tumoral phenotype ( 11 , 25 , 52 , 53 , 57 , 59 ). Anti-inflammatory approaches in cancer, such as aspirin, have been shown to trigger SPM production that stimulates cancer resolution by targeting macrophage subsets ( 36 ).…”

“…Strategies targeting inflammation to prevent an adequate microenvironment for tumor growth and escape have been mostly concentrated on myeloid cells. Again, the depletion of macrophages increased CD8 + T cells, and impairment of phagocytosis was associated with an increased IFN-γ T-cell response ( 57 , 59 ). In murine models, anti-inflammatory drugs have been associated with a more important CD4/CD8 T-cell infiltration in spleen after tumor rejection ( 49 ).…”

Nonresolving inflammation redux

“…Likewise, an agonistic anti-CD40 mAb combined with a CSF-1R inhibitor drove TAMs in a mouse melanoma model to secrete TNFα, IL-6, and IL-12 and suppressed tumor growth ( Perry et al., 2018 ). Interference with the anti-phagocytic effect of tumor cell CD47 acting on macrophage SIRPα shrank tumors in mice and people and improved responses to chemo- and immunotherapy ( Advani et al., 2018 ; Kosaka et al., 2021 ; Weiskopf et al., 2013 ). Prostate cancer cell-derived IL-1β increased MARCO expression on macrophages; MARCO engagement with lipids induced macrophages to make CCL6; CCL6 promoted prostate cancer cell metastasis; and anti-MARCO antibody reduced tumor growth ( Masetti et al., 2022 ).…”

DNA Damage and Activation of cGAS/STING Pathway Induce Tumor Microenvironment Remodeling

“…In pre-clinical models of ovarian tumor and aggressive lung cancer, combination therapy including anti-IL-10, 2′3′-cGAMP, and anti-PD-L1 targeting innate and adaptive immunity dramatically decreased MDSCs and improved DC activation and T-cell infiltration ( Hartl et al, 2019 ). Breast tumor patients with high expression of CD47 showed poor survival and prognosis; cGAMP and anti-CD47 combination therapy effectively suppressed tumor growth, whereas monotherapy with anti-CD47 did not inhibit tumors ( Kosaka et al, 2021 ). The flavone-8-acetic acid derivative 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a selective STING agonist of mice, has outstanding antitumor characteristics in multiple tumor models ( Curran et al, 2016 ; Weiss et al, 2017 ; Liu et al, 2020 ; Xu et al, 2021 ).…”