Opportunities and challenges of CD47-targeted therapy in cancer immunotherapy

Abstract

Cancer immunotherapy has emerged as a promising strategy for the treatment of cancer, with the tumor microenvironment (TME) playing a pivotal role in modulating the immune response. CD47, a cell surface protein, has been identified as a crucial regulator of the TME and a potential therapeutic target for cancer therapy. However, the precise functions and implications of CD47 in the TME during immunotherapy for cancer patients remain incompletely understood. This comprehensive review aims to provide an overview of CD47's multifaced role in TME regulation and immune evasion, elucidating its impact on various types of immunotherapy outcomes, including checkpoint inhibitors and CAR T-cell therapy. Notably, CD47-targeted therapies offer a promising avenue for improving cancer treatment outcomes, especially when combined with other immunotherapeutic approaches. The review also discusses current and potential CD47-targeted therapies being explored for cancer treatment and delves into the associated challenges and opportunities inherent in targeting CD47. Despite the demonstrated effectiveness of CD47-targeted therapies, there are potential problems, including unintended effects on healthy cells, hematological toxicities, and the development if resistance. Consequently, further research efforts are warranted to fully understand the underlying mechanisms of resistance and to optimize CD47-targeted therapies through innovative combination approaches, ultimately improving cancer treatment outcomes. Overall, this comprehensive review highlights the significance of CD47 as a promising target for cancer immunotherapy and provides valuable insight into the challenges and opportunities in developing effective CD47-targeted therapies for cancer treatment.

Keywords: CAR T-cell therapy; CD47; CD47-targeted therapies; Cancer cell; Cancer immunotherapy; Cancer treatment outcomes; Checkpoint inhibitors; Immune evasion; Macrophage; Tumor microenvironment.

Figure 1. CD47-SIRPα blockade in activating the “don’t eat me” signal and enhancing anti-tumor immunity. (A) The interaction between CD47, expressed on the surface of cancer cells, and SIRPα on macrophages sends a “don’t eat me” signal, inhibiting phagocytosis of the cancer cell by the macrophage. This binding of CD47 and SIRPα allows cancer cells to evade detection by macrophages, which perceive them as “self” and do not attack them. (B) Disrupting the CD47-SIRPα interaction between cancer cells and macrophages promotes phagocytosis. Treatment with either anti-CD47 or anti-SIRPα mAbs blocks the CD47-SIRPα interaction, leading to the activation of an “eat me” signal that enables macrophages to recognize cancer cells as non-self and initiates phagocytosis. Targeted therapies that disrupt the CD47-SIRPα interaction have the potential to improve the efficacy of cancer immunotherapy by enabling macrophages to overcome the “don’t eat me” signal and phagocytose cancer cells.

Figure 2. CD47-targeted therapies present challenges and potential unintended effects due to the expression of CD47 on healthy cells. CD47 blockade can cause anemia and hematological toxicities. However, CD47 is not the only immune checkpoint molecule involved in immune evasion, and targeting other molecules such as PD-L1, CTLA-4, LAG-3, TIM-3, and IDO, either alone or in combination with CD47, has shown promise in preclinical and clinical studies. Resistance to CD47-targeted therapies has also been observed, and tumor heterogeneity and the presence of immune-suppressive cells and factors in the TME can interfere with the effectiveness of CD47-targeted therapies. Therefore, combination approaches and further research are needed to fully understand the mechanisms of resistance.