The field of cancer treatment has witnessed a remarkable evolution with the advent of immune checkpoint inhibitors, notably targeting programmed cell death receptor-1 (PD-1) and programmed cell death ligand-1 (PD-L1).
However, the quest for more effective therapeutic modalities has recently steered pharmaceutical communities toward innate immunity checkpoints. Among these, the immune checkpoint of macrophages, specifically the cluster of differentiation (CD) 47/signal regulatory protein alpha (SIRPα) pathway, has emerged as a focal point of interest.
Decoding CD47: From Red Blood Cells to Tumor Antigen
CD47, originally recognized as integrin-associated protein, stands as a 50 kDa plasma membrane molecule exhibiting a complex structure. Its composition includes an extracellular variable region interacting with ligands, a transmembrane region with hydrophobic segments, and a hydrophilic carboxy-terminal intracellular region.
Initially identified as a transmembrane protein in red blood cells (RBCs), CD47’s widespread expression in various human cell types, including cancer cells, has become evident.
Notably, CD47 surfaced as a tumor antigen in human ovarian cancer, paving the way for further exploration in hematological malignancies such as non-Hodgkin’s lymphomas (NHL), T-cell lymphoma, acute myeloid leukemia (AML), and myelodysplastic syndrome (MDS).
Interplay of CD47: Ligands, Receptors, and Intricate Signaling Pathways
CD47’s functionality extends beyond its structural intricacies, as it actively engages with a myriad of extracellular ligands and intracellular partners. Key among these are signal regulatory protein alpha (SIRPα), thrombospondin-1 (TSP-1), integrins (α2β1, α4β1, α5β1, α6β1), SIRPγ, CD36, and CD95. While interactions with SIRPα, TSP-1, and integrins have been extensively studied, the versatile engagement of CD47 in various pathways underscores its multifaceted role.
SIRPα, belonging to the signal regulatory protein (SIRP) family, plays a pivotal role in the CD47/SIRPα axis. Comprising an intracellular domain with an immunoreceptor tyrosine-based inhibitor motif (ITIM), a transmembrane-spanning region, and three extracellular immunoglobulin superfamily domains, SIRPα orchestrates the cellular response upon CD47 binding.
The phosphorylation of ITIM triggers the recruitment and activation of phosphatases, such as Src homology phosphatase (SHP)-1 and SHP-2, culminating in the activation of the “don’t eat me” signal predominantly in myeloid cells, including macrophages.
Functional Dynamics of CD47/SIRPα Axis in Tumor Cells: Deciphering the Complexity
The elevation of CD47 expression in leukemic cancer cells serves as a strategic defense mechanism, aiding in the evasion of macrophage-mediated phagocytosis. The CD47/SIRPα axis is now recognized as a linchpin in the treatment, prognosis, and diagnosis of diverse malignancies, with a spotlight on its therapeutic implications.
… Here is a more detailed explanation of the passage:
Leukemic cancer cells have a clever way of avoiding destruction by macrophages, which are immune cells that engulf and eliminate abnormal cells. This defense mechanism involves the overexpression of a protein called CD47 on the surface of leukemic cells. CD47 interacts with another protein called SIRPα on the surface of macrophages, sending a “don’t eat me” signal that effectively prevents the macrophages from phagocytosing the cancer cells.
The CD47/SIRPα axis plays a crucial role in the development, progression, and prognosis of various types of cancer. This interaction between CD47 and SIRPα has emerged as a promising target for cancer immunotherapy, a treatment approach that harnesses the power of the immune system to fight cancer. By blocking the CD47/SIRPα interaction, scientists can unleash the phagocytic potential of macrophages and enhance their ability to eliminate cancer cells.
The CD47/SIRPα axis also holds significance in cancer diagnosis. The expression levels of CD47 and SIRPα can be used to predict the aggressiveness of certain cancers and guide treatment decisions. For instance, high levels of CD47 expression are associated with poorer outcomes in patients with certain types of leukemia.
In summary, the CD47/SIRPα axis is a critical regulator of cancer cell survival and immune evasion. Targeting this pathway offers a promising avenue for cancer immunotherapy and holds potential for improving cancer diagnosis and prognosis.
Recent research has unearthed five primary mechanisms driving the CD47/SIRPα axis in tumor cells. Suppression of the CD47-SIRPα interaction emerges as a potent strategy, promoting macrophage phagocytosis. Full activation of macrophages necessitates a dual condition: blockade of the CD47 “don’t eat me” signal and activation of the Fc receptor “eat me” signal, each providing a limited macrophage activation individually. In addition to macrophages, blocking the CD47/SIRPα axis induces an antitumor state in tumor-associated macrophages, enhancing tumor macrophage recruitment.
Furthermore, inhibition of the SIRPα/CD47 axis facilitates phagocytosis by dendritic cells, fostering subsequent antigen presentation to CD8 + T-cells and instigating an adaptive antitumor immune response. Beyond these, CD47 antagonists leverage natural killer cell-mediated antibody-dependent cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) to annihilate tumor cells.
Notably, CD47 antagonists exhibit the capacity to promote tumor cell death, reduce tumor cell proliferation, and impede tumor cell migration, expanding the repertoire of potential therapeutic interventions. Additionally, high CD47 expression serves as a prognostic marker across various cancers, indicating a poor outcome in acute myeloid leukemia (AML), chronic myelogenous leukemia, non-Hodgkin’s lymphomas (NHL), and several solid tumors.
Beyond Treatment: CD47’s Role in Diagnosis and Clinical Implications
Apart from its therapeutic implications, CD47 has emerged as a diagnostic tool in various cancers, including non-small cell lung cancer, renal cell tumors, and hematological tumors. The multifaceted role of CD47, spanning diagnosis, prognosis, and treatment, underscores its significance in the oncological landscape.
Clinical Development of CD47/SIRPα Antibodies: Navigating the Future
The past decade has witnessed a surge in patent applications for CD47 antagonists, with the top licensing authorities, including the United States, the World Intellectual Property Organization, the European Patent Office, Japan, and China, holding a significant share. More than two-thirds of all patents pertain to CD47 antagonists, with many progressing into clinical trials.
This burgeoning field is currently classified into five categories: CD47 monoclonal antibody, CD47-targeted bispecific antibody, SIRPα/Fc fusion protein antibody, CD47 small-molecule inhibitor, and CD47 antibody–drug conjugate. While CD47 small-molecule inhibitors and antibody–drug conjugates for hematologic malignancies are yet to be publicly available in clinical trials, the focus herein lies on the first three categories.
Clinical investigations employing CD47 monoclonal antibodies have yielded promising results, accompanied by common adverse events such as anemia and thrombocytopenia. This is attributed to the expression of CD47 on erythrocytes and platelets, making them susceptible to attack via direct binding or activation of NK cells and macrophages through Fc-mediated ADCC or CDC.
In a bid to enhance treatment efficacy and mitigate toxicity, researchers have pioneered CD47-targeted bispecific antibodies and SIRPα/Fc fusion protein antibodies. The synergistic effect of bispecific antibodies, targeting CD47 alongside other tumor antigens, holds promise in augmenting safety and efficacy by preferentially targeting tumor cells.
SIRPα/Fc fusion protein antibodies, by destroying CD47/SIRPα binding and generating activating prophagocytic signals via Fc receptors, present an innovative approach with negligible binding to RBCs or blood platelets, distinguishing them from anti-CD47 monoclonal antibodies.
Towards the Future: CD47/SIRPα Axis as a Hematological Immunotherapeutic Target
The CD47/SIRPα axis has emerged as a beacon of hope in the realm of hematological malignancies, setting the stage for a comprehensive overview of CD47 antagonist clinical research frontiers. Collating information from reputable databases, including PubMed, Researchgate, the US national clinical trials registry (NCT) system, and the China drug trials registry (CTR) system, this article provides a detailed summary of ongoing clinical trials aimed at unraveling the potential of CD47 antagonists in treating lymphomas and hematological malignancies.
In conclusion, the journey from understanding the molecular intricacies of CD47 to exploring its clinical implications and delving into the development of targeted antibodies signifies a paradigm shift in cancer immunotherapy. The CD47/SIRPα axis, with its multifaceted roles in immune evasion and tumor cell fate determination, emerges as a promising avenue for future breakthroughs in hematological malignancy treatment. As ongoing clinical trials unfold, the intricate dance between CD47 and immune cells promises to revolutionize the landscape of cancer therapeutics, offering new hope for patients and clinicians alike.
reference link: https://biomarkerres.biomedcentral.com/articles/10.1186/s40364-023-00456-x#Abs1