Explore the vast range of titles available.

Tumour cell phagocytosis by antigen presenting cells (APCs) is critical to the generation of antitumour immunity. However, cancer cells can evade phagocytosis by upregulating anti-phagocytosis molecule CD47. Here, we show that CD47 blockade alone is inefficient in stimulating glioma cell phagocytosis. However, combining CD47 blockade with temozolomide results in a significant pro-phagocytosis effect due to the latter’s ability to induce endoplasmic reticulum stress response. Increased tumour cell phagocytosis subsequently enhances antigen cross-presentation and activation of cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS–STING) in APCs, resulting in more efficient T cell priming. This bridging of innate and adaptive responses inhibits glioma growth, but also activates immune checkpoint. Sequential administration of an anti-PD1 antibody overcomes this potential adaptive resistance. Together, these findings reveal a dynamic relationship between innate and adaptive immune regulation in tumours and support further investigation of phagocytosis modulation as a strategy to enhance cancer immunotherapy responses. Professional antigen presenting cells (APCs) are deterred from phagocytosing cancer cells that express CD47. Here, the authors show that in glioblastoma mouse models, temozolomide improves the phagocytosis effect of CD47 blockade in APCs and results in the activation of adaptive anti-tumour responses.

CD47 is the only 5-transmembrane (5-TM) spanning receptor of the immune system. Its extracellular domain (ECD) is a cell surface marker of self that binds SIRPα and inhibits macrophage phagocytosis, and cancer immuno-therapy approaches in clinical trials are focused on blocking CD47/SIRPα interaction. We present the crystal structure of full length CD47 bound to the function-blocking antibody B6H12. CD47 ECD is tethered to the TM domain via a six-residue peptide linker ( 114 RVVSWF 119 ) that forms an extended loop (SWF loop), with the fundamental role of inserting the side chains of W118 and F119 into the core of CD47 extracellular loop region (ECLR). Using hydrogen-deuterium exchange and molecular dynamics simulations we show that CD47’s ECLR architecture, comprised of two extracellular loops and the SWF loop, creates a molecular environment stabilizing the ECD for presentation on the cell surface. These findings provide insights into CD47 immune recognition, signaling and therapeutic intervention. CD47 is a transmembrane receptor involved in the regulation of various signalling pathways and a promising target for immuno-oncology therapeutics. Here, the authors present the crystal structure of full-length human CD47 and provide insights into the molecular mechanism of CD47-mediated signalling.

Therapeutic antitumor antibodies treat cancer by mobilizing both innate and adaptive immunity. CD47 is an antiphagocytic ligand exploited by tumor cells to blunt antibody effector functions by transmitting an inhibitory signal through its receptor signal regulatory protein alpha (SIRPα). Interference with the CD47–SIRPα interaction synergizes with tumor-specific monoclonal antibodies to eliminate human tumor xenografts by enhancing macrophage-mediated antibody-dependent cellular phagocytosis (ADCP), but synergy between CD47 blockade and ADCP has yet to be demonstrated in immunocompetent hosts. Here, we show that CD47 blockade alone or in combination with a tumor-specific antibody fails to generate antitumor immunity against syngeneic B16F10 tumors in mice. Durable tumor immunity required programmed death-ligand 1 (PD-L1) blockade in combination with an antitumor antibody, with incorporation of CD47 antagonism substantially improving response rates. Our results highlight an underappreciated contribution of the adaptive immune system to anti-CD47 adjuvant therapy and suggest that targeting both innate and adaptive immune checkpoints can potentiate the vaccinal effect of antitumor antibody therapy.

CD47 is an immunoglobulin that is overexpressed on the surface of many types of cancer cells. CD47 forms a signaling complex with signal-regulatory protein α (SIRPα), enabling the escape of these cancer cells from macrophage-mediated phagocytosis. In recent years, CD47 has been shown to be highly expressed by various types of solid tumors and to be associated with poor patient prognosis in various types of cancer. A growing number of studies have since demonstrated that inhibiting the CD47-SIRPα signaling pathway promotes the adaptive immune response and enhances the phagocytosis of tumor cells by macrophages. Improved understanding in this field of research could lead to the development of novel and effective anti-tumor treatments that act through the inhibition of CD47 signaling in cancer cells. In this review, we describe the structure and function of CD47, provide an overview of studies that have aimed to inhibit CD47-dependent avoidance of macrophage-mediated phagocytosis by tumor cells, and assess the potential and challenges for targeting the CD47-SIRPα signaling pathway in anti-cancer therapy.

Trastuzumab, a targeted anti-human epidermal-growth-factor receptor-2 (HER2) monoclonal antibody, represents a mainstay in the treatment of HER2-positive (HER2⁺) breast cancer. Although trastuzumab treatment is highly efficacious for early-stage HER2⁺ breast cancer, the majority of advanced-stage HER2⁺ breast cancer patients who initially respond to trastuzumab acquire resistance to treatment and relapse, despite persistence of HER2 gene amplification/overexpression. Here, we sought to leverage HER2 overexpression to engage antibody-dependent cellular phagocytosis (ADCP) through a combination of trastuzumab and anti-CD47 macrophage checkpoint immunotherapy. We have previously shown that blockade of CD47, a surface protein expressed by many malignancies (including HER2⁺ breast cancer), is an effective anticancer therapy. CD47 functions as a “don’t eat me” signal through its interaction with signal regulatory protein-α (SIRPα) on macrophages to inhibit phagocytosis. Hu5F9-G4 (magrolimab), a humanized monoclonal antibody against CD47, blocks CD47’s “don’t eat me” signal, thereby facilitating macrophage-mediated phagocytosis. Preclinical studies have shown that combining Hu5F9-G4 with tumor-targeting antibodies, such as rituximab, further enhances Hu5F9-G4’s anticancer effects via ADCP. Clinical trials have additionally demonstrated that Hu5F9-G4, in combination with rituximab, produced objective responses in patients whose diffuse large B cell lymphomas had developed resistance to rituximab and chemotherapy. These studies led us to hypothesize that combining Hu5F9-G4 with trastuzumab would produce an anticancer effect in antibody-dependent cellular cytotoxicity (ADCC)-tolerant HER2⁺ breast cancer. This combination significantly suppressed the growth of ADCC-tolerant HER2⁺ breast cancers via Fc-dependent ADCP. Our study demonstrates that combining trastuzumab and Hu5F9-G4 represents a potential new treatment option for HER2⁺ breast cancer patients, even for patients whose tumors have progressed after trastuzumab.

New strategies for cancer immunotherapy are needed since most solid tumors do not respond to current approaches. Here we used epithelial cell adhesion molecule EpCAM (a tumor-associated antigen highly expressed on common epithelial cancers and their tumor-initiating cells) aptamer-linked small-interfering RNA chimeras (AsiCs) to knock down genes selectively in EpCAM⁺ tumors with the goal of making cancers more visible to the immune system. Knockdown of genes that function in multiple steps of cancer immunity was evaluated in aggressive triple-negative and HER2⁺ orthotopic, metastatic, and genetically engineered mouse breast cancer models. Gene targets were chosen whose knockdown was predicted to promote tumor neoantigen expression (Upf2, Parp1, Apex1), phagocytosis, and antigen presentation (Cd47), reduce checkpoint inhibition (Cd274), or cause tumor cell death (Mcl1). Four of the six AsiC (Upf2, Parp1, Cd47, and Mcl1) potently inhibited tumor growth and boosted tumor-infiltrating immune cell functions. AsiC mixtures were more effective than individual AsiC and could synergize with anti–PD-1 checkpoint inhibition.

Atherosclerotic lesions in mice and humans switch on a ‘don’t eat me’ signal—expression of CD47—that prevents effective removal of diseased tissue; anti-CD47 antibody therapy can normalize this defective efferocytosis, with beneficial results in several mouse models of atherosclerosis. Pathogenesis mechanisms in atherosclerosis Nicholas Leeper and colleagues demonstrate that atherosclerotic lesions in mice and humans switch on a 'don't eat me' signal — in the form of expression of the anti-phagocytic transmembrane protein CD47 — that prevents effective removal of diseased tissue. They show that administration of anti-CD47 antibodies can normalize this defective phagocytic clearance (or ‘efferocytosis’) with beneficial results in several mouse models of atherosclerosis. These results suggest that targeted pro-efferocytic therapies could have potential in cardiovascular diseases. Atherosclerosis is the disease process that underlies heart attack and stroke 1 . Advanced lesions at risk of rupture are characterized by the pathological accumulation of diseased vascular cells and apoptotic cellular debris 2 . Why these cells are not cleared remains unknown 3 . Here we show that atherogenesis is associated with upregulation of CD47, a key anti-phagocytic molecule that is known to render malignant cells resistant to programmed cell removal, or ‘efferocytosis’ 4 , 5 , 6 , 7 . We find that administration of CD47-blocking antibodies reverses this defect in efferocytosis, normalizes the clearance of diseased vascular tissue, and ameliorates atherosclerosis in multiple mouse models. Mechanistic studies implicate the pro-atherosclerotic factor TNF-α as a fundamental driver of impaired programmed cell removal, explaining why this process is compromised in vascular disease. Similar to recent observations in cancer 5 , impaired efferocytosis appears to play a pathogenic role in cardiovascular disease, but is not a fixed defect and may represent a novel therapeutic target.

Antibodies targeting the T-cell immune checkpoint cytotoxic T-lymphocyte antigen-4 (CTLA4) enhance the effectiveness of radiotherapy for melanoma patients, but many remain resistant. To further improve response rates, we explored combining anti-CTLA4 blockade with antisense suppression of CD47, an inhibitory receptor on T cells that limit T-cell receptor signaling and killing of irradiated target cells. Human melanoma data from The Cancer Genome Atlas revealed positive correlations between CD47 mRNA expression and expression of T-cell regulators including CTLA4 and its counter receptors CD80 and CD86. Antisense suppression of CD47 on human T cells in vitro using a translational blocking morpholino (CD47 m) alone or combined with anti-CTLA4 enhanced antigen-dependent killing of irradiated melanoma cells. Correspondingly, the treatment of locally irradiated B16F10 melanomas in C57BL/6 mice using combined blockade of CD47 and CTLA4 significantly increased the survival of mice relative to either treatment alone. CD47 m alone or in combination with anti-CTLA4 increased CD3+ T-cell infiltration in irradiated tumors. Anti-CTLA4 also increased CD3+ and CD8+ T-cell infiltration as well as markers of NK cells in non-irradiated tumors. Anti-CTLA4 combined with CD47 m resulted in the greatest increase in intratumoral granzyme B, interferon-γ, and NK-cell marker mRNA expression. These data suggest that combining CTLA4 and CD47 blockade could provide a survival benefit by enhancing adaptive T- and NK-cell immunity in irradiated tumors.

Background Targeting oncogenic histone modification by histone deacetylase inhibitors (HDACis) demonstrates promising prospects in clinical cancer treatment, whereas a notable proportion of patients cannot benefit from HDACi therapy. This study aims to explore how HDACi influences the tumor microenvironment, in order to identify potential targets for reversing the resistance to HDACi therapies. Methods Macrophage infiltration was compared between HDACi-responding and HDACi-nonresponding cancer patients. The impact of HDACis on the phagocytic capacity of macrophages was investigated through macrophage-tumor cell co-culture system. CD47 expression in tumor cell lines and patient-derived organoids was evaluated by quantitative polymerase chain reaction (QPCR) and flow cytometry. Mechanistic studies were conducted through co-immunoprecipitation (co-IP) and chromatin immunoprecipitation (ChIP). The synergistic effect of HDACis and CD47 neutralizing antibody was assessed in subcutaneous murine tumor models. Bioinformatics approaches were adopted to analyze how macrophage infiltration determines the prognostic significance of CD47 expression in cancer patients. Results High macrophage infiltration is a determinant of therapeutic non-response to HDACi, cancer patients who did not respond to HDACi exhibit massive infiltration of tumor-associated macrophages (TAMs). TAM depletion reversed the resistance to HDACi therapy. Mechanistically, HDACi impaired the phagocytic capacity of macrophages against tumor cells through epigenetically upregulating CD47 expression. Reciprocally, HDACi-upregulated CD47 polarized macrophages towards a pro-tumor M2 phenotype through SIRPα ligation. In tumor-bearing mice, HDACi monotherapy only marginally delayed tumor progression, while the concurrent neutralization of CD47 exhibited potent anti-tumor effect through re-educating TAMs towards a tumoricidal phenotype. In cancer patients, CD47 was found to determine the prognostic significance of TAMs. Conclusions Our study offers a rationale for targeting macrophage infiltration or blocking CD47 to sensitize HDACi therapies in cancer patients.