CD47–signal regulatory protein-α (SIRPα) interactions form a barrier for antibody-mediated tumor cell destruction

Abstract

Monoclonal antibodies are among the most promising therapeutic agents for treating cancer. Therapeutic cancer antibodies bind to tumor cells, turning them into targets for immune-mediated destruction. We show here that this antibody-mediated killing of tumor cells is limited by a mechanism involving the interaction between tumor cell-expressed CD47 and the inhibitory receptor signal regulatory protein-α (SIRPα) on myeloid cells. Mice that lack the SIRPα cytoplasmic tail, and hence its inhibitory signaling, display increased antibody-mediated elimination of melanoma cells in vivo. Moreover, interference with CD47-SIRPα interactions by CD47 knockdown or by antagonistic antibodies against CD47 or SIRPα significantly enhances the in vitro killing of trastuzumab-opsonized Her2/Neu-positive breast cancer cells by phagocytes. Finally, the response to trastuzumab therapy in breast cancer patients appears correlated to cancer cell CD47 expression. These findings demonstrate that CD47-SIRPα interactions participate in a homeostatic mechanism that restricts antibody-mediated killing of tumor cells. This provides a rational basis for targeting CD47-SIRPα interactions, using for instance the antagonistic antibodies against human SIRPα described herein, to potentiate the clinical effects of cancer therapeutic antibodies.antibody-dependent cellular cytotoxicity | neutrophil | immunoreceptor | Fc-receptor

Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma

“…41 Moreover, targeting the CD47-SIRP a axis has now been shown to increase efficacy of several therapeutic antibodies. 42,43 CD47 is described to be highly expressed on CD38 C MM cells, 44 suggesting that inhibition of the CD47-SIRP a axis might be an interesting therapeutic approach in combination with DARA.…”

Cd47-Sirpα interaction and IL-10 constrain inflammation-induced macrophage phagocytosis of healthy self-cells

“…conjunction with therapeutic anticancer antibodies (4,9,(16)(17)(18)(19)(20)(21). Conversely, the lack of a compatible CD47 to ligate the recipient SIRPα is considered to be associated with tissue rejection in xenotransplantation (22)(23)(24)(25).…”

CD47, a multi-facetted target for cancer immunotherapy

“…Of note, the functional and clinical implications of the respective isoforms in normal biology as well as in cancer remain unclear. CD47 was first identified as an antigen expressed on ovarian carcinoma (Poels et al, 1986), but is overexpressed in many solid tumors and hematologic malignancies Chao et al, 2010a;Chao et al, 2011a;Zhao et al, 2011;Willingham et al, 2012;Rendtlew Danielsen et al, 2007;Edris et al, 2012). High levels of CD47 are also found on human bladder tumor-initiating cells and leukemic stem cells Chan et al, 2009).…”

“…Further, increased protein expression of CD47 associates with poor clinical outcome in among others ovarian cancer and glioblastoma, Chao et al, 2010a;Chao et al, 2011a;Willingham et al, 2012). Moreover, high CD47 levels associate with various adverse characteristics, such as developmental stage of the tumor, adverse molecular subtype, and resistance to therapy (Rendtlew Danielsen et al, 2007;Chao et al, 2010a;Zhao et al, 2011;. Interestingly, high levels of CD47 expression in the bone marrow of breast cancer patients lead to a significant reduction in disease free survival (Nagahara et al, 2010).…”

“…This function of CD47 in cellular turn-over was first established in red blood cells almost 2 decades ago and is now held to be a general homeostatic system (Oldenborg et al, 2000). Both solid and hematologic malignancies overexpress CD47 and, thereby, essentially hijack this homeostatic system to evade phagocytic clearance Chao et al, 2011b;Jaiswal et al, 2009;Chao et al, 2010a;Chao et al, 2011a;Zhao et al, 2011;Rendtlew Danielsen et al, 2007;. Therapeutic interventions that block CD47-SIRPα interaction have been found to promote phagocytic elimination of such CD47 overexpressing tumor cells and are poised for clinical evaluation (Chao et al, 2010a;Tseng et al, 2013;Theocharides et al, 2012;Majeti et al, 2009;Chao et al, 2011b;Chao et al, 2011a;Willingham et al, 2012;Edris et al, 2012).…”