Journal
MOLECULAR CANCER THERAPEUTICS
Volume 20, Issue 6, Pages 961-974Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-21-0041
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- NIH NRSA [T32CA236734]
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While immunotherapy has revolutionized the treatment of many types of advanced cancer, most patients still do not derive benefit. Innate immune checkpoint inhibitors are a promising new target that can disrupt inhibitory interactions between tumor and both phagocytes and natural killer cells. This area of drug development targeting phagocytosis and natural killer-cell checkpoints could revolutionize immune-based cancer therapies.
While immunotherapy has revolutionized the treatment of many types of advanced cancer, most patients still do not derive benefit. The currently available immune checkpoint inhibitors target the adaptive immune system, generating a T-cell antitumor response. However, an antitumor immune response depends on a complex interplay of both innate and adaptive immune cells. The innate immune system is a promising new target, and innate immune checkpoint inhibitors can disrupt inhibitory interactions (don't eat me signals) between tumor and both phagocytes and natural killer cells. The checkpoint inhibitor may also provide a stimulatory interaction (eat me signal), or this can be achieved through use of combination therapy. This generates antitumor effector functions including phagocytosis, natural cytotoxicity, antibodydependent effects, and synergistic activation of the adaptive immune system via antigen presentation. This is a rapidly expanding area of drug development, either alone or in combination (with anticancer antibodies or adaptive immune checkpoint inhibitors). Here, we comprehensively review the mechanism of action and up-to-date solid tumor clinical trial data of the drugs targeting phagocytosis checkpoints (SIRPa/CD47, LILRB1/MHC-I, and LILRB2/MHC-I) and natural killer-cell checkpoints (TIGIT/CD112 thorn CD155, PVRIG/CD112, KIRs/MHC-I, and NKG2A-CD94/HLA-E). Innate immune checkpoint inhibitors could once again revolutionize immune-based cancer therapies.
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