Emerging phagocytosis checkpoints in cancer immunotherapy

Abstract

Cancer immunotherapy, mainly including immune checkpoints-targeted therapy and the adoptive transfer of engineered immune cells, has revolutionized the oncology landscape as it utilizes patients’ own immune systems in combating the cancer cells. Cancer cells escape immune surveillance by hijacking the corresponding inhibitory pathways via overexpressing checkpoint genes. Phagocytosis checkpoints, such as CD47, CD24, MHC-I, PD-L1, STC-1 and GD2, have emerged as essential checkpoints for cancer immunotherapy by functioning as “don’t eat me” signals or interacting with “eat me” signals to suppress immune responses. Phagocytosis checkpoints link innate immunity and adaptive immunity in cancer immunotherapy. Genetic ablation of these phagocytosis checkpoints, as well as blockade of their signaling pathways, robustly augments phagocytosis and reduces tumor size. Among all phagocytosis checkpoints, CD47 is the most thoroughly studied and has emerged as a rising star among targets for cancer treatment. CD47-targeting antibodies and inhibitors have been investigated in various preclinical and clinical trials. However, anemia and thrombocytopenia appear to be formidable challenges since CD47 is ubiquitously expressed on erythrocytes. Here, we review the reported phagocytosis checkpoints by discussing their mechanisms and functions in cancer immunotherapy, highlight clinical progress in targeting these checkpoints and discuss challenges and potential solutions to smooth the way for combination immunotherapeutic strategies that involve both innate and adaptive immune responses.

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“…Furthermore, CD47 blockade facilitates phagocytosis of cancer cells by DCs, thereby increasing antigen presentation by DCs to T cells. 185,190,191 The first antibody targeting CD47, Hu5F9-G4, was used in children with brain tumors and had a curative effect in five different cases. 190,192 Although CD47 targeting antibodies have shown great preclinical success, there are some important clinical challenges associated with it.…”

“…185,190,191 The first antibody targeting CD47, Hu5F9-G4, was used in children with brain tumors and had a curative effect in five different cases. 190,192 Although CD47 targeting antibodies have shown great preclinical success, there are some important clinical challenges associated with it. CD47 is not only expressed on cancer cells, but also on red blood cells (RBC) and T cells, thereby creating serious immune-related adverse effect (irAE) issues with anti-CD47 antibodies.…”

“…185,191 CD24 is a promising target for cancer immunotherapy, due to its expression on immune cells however therapies targeting it might also be susceptible to adverse effects owing to its ubiquitous expression patterns. 190 Finally, MHC-I targeting can also enhance phagocytosis of cancer cells. MHC-I, which is expressed on cancer cells, binds via its subunit β2M, to its receptor leukocyte immunoglobulin-like receptor B1 (LILRB1).…”

“…MHC-I, which is expressed on cancer cells, binds via its subunit β2M, to its receptor leukocyte immunoglobulin-like receptor B1 (LILRB1). 190,191 The MHC-I-LILRB1 axis plays a crucial role in inhibiting phagocytosis and therefore, blocking either MHC-I or LILRB1 can promote phagocytosis. However, as MHC-I is important in antigen presentation, targeting MHC-I may also cause loss of T-cell recognition of antigens.…”

“…Therefore, CD47 targeting antibodies can increase phagocytosis of cancer cells, enhance a pro‐inflammatory phenotype and enable cancer cell death inside the phagocytic vesicles or via pro‐inflammatory factors. Furthermore, CD47 blockade facilitates phagocytosis of cancer cells by DCs, thereby increasing antigen presentation by DCs to T cells 185,190,191 . The first antibody targeting CD47, Hu5F9‐G4, was used in children with brain tumors and had a curative effect in five different cases 190,192 .…”