CD47 blockade triggers T cell–mediated destruction of immunogenic tumors

Abstract

Macrophage phagocytosis of tumor cells mediated by CD47-specific blocking antibodies has been proposed to be the major effector mechanism in xenograft models. Using syngeneic immunocompetent tumor models, we reveal that in the therapeutic effects of CD47 blockade depend on dendritic cell (DC) but not macrophage cross-priming of T cell responses in immunocompetent mice. The therapeutic effects of anti-CD47 antibody therapy were abrogated in T cell-deficient mice. In addition, the anti-tumor effects of CD47 blockade required expression of the cytosolic DNA sensor STING, but neither MyD88 nor TRIF, in CD11c+ cells, suggesting that cytosolic sensing of DNA from tumor cells is enhanced by anti-CD47 treatment, further bridging the innate and adaptive responses. Notably, the timing of administration of standard chemotherapy markedly impacted the induction of anti-tumor T cell responses by CD47 blockade. Together, our findings indicate that CD47 blockade drives T cell-mediated elimination of immunogenic tumors.

HIF-1 regulates CD47 expression in breast cancer cells to promote evasion of phagocytosis and maintenance of cancer stem cells

“…CRT expression was induced by exposure of cardiomyocytes to hypoxia and reoxygenation (51), suggesting that the increased phagocytosis of NTC and DKD subclones after hypoxic exposure may be due to HIF-independent CRT expression, but further studies are required to test this hypothesis. A recent report demonstrated that CD47 blockade also promotes T-cell-mediated elimination of immunogenic tumors (52) and HIF-1 is known to inhibit effector T cells through the production of adenosine (23,47), suggesting that HIF inhibitors may improve the response to CD47 blockade both by inhibiting CD47 expression and by disinhibiting T-cell-mediated antitumor immunity.…”

The innate immune receptor Dectin-2 mediates the phagocytosis of cancer cells by Kupffer cells for the suppression of liver metastasis

“…Of note, it has been reported that treatment with an anti-CD47 antibody effectively suppresses in vivo tumor growth without coadministration of other chemotherapeutic agents (38,39). Given that CD47 is a well-known "don't eat me" signal for inhibiting phagocytosis (40), the uptake of cancer cells by phagocytes is a promising target for anticancer therapy, particularly when combined with a method that accelerates the cancer cell phagocytosis.…”

Targeting CD47: the achievements and concerns of current studies on cancer immunotherapy

“…Syngeneic C57BL/6 model exhibits only mild and transient tumor inhibition upon multiple doses of anti-mouse CD47 mAb MIAP301 (19). Similarly, syngeneic FVB model also showed insignificant tumor inhibition upon MIAP301 administration (2).…”

“…However, the rationale and potential pitfalls of using NSG mice in CD47 research have not been well discussed; and therefore, whether it is the best choice for the study deserves further consideration. Concerns have been raised over the suitableness of the Sirpα NOD allele in NSG animals to the CD47 study (14,19). The binding affinity between human CD47 and Sirpα NOD is about 10 times greater than with human SIRPα (20).…”

“…To elicit a robust immune response in immunocompetent animals, the use of appropriate Fc fragment is necessary. One syngeneic study administered an anti-mouse CD47 mAb MIAP301 of rat IgG2a into mouse immune system (19). Without appropriate Fc, the resulted immune response could also be substantially underestimated.…”