Shaping neutrophil responses against cancer The role of integrin regulation

Neutrophils, the most abundant cell type in blood circulation, play a crucial role in immune defense against pathogens and malignant cells. Accounting for up to 70% of total leukocytes, neutrophils are continuously generated in large numbers in the bone marrow. Yet, they exhibit a short half-life, lasting up to 24-48 hours with a brief circulation of 8-10 hours in the bloodstream. This short lifespan is purposeful, as they serve as the first line of defense against pathogens, being recruited to infection sites to eliminate pathogens before inflammation occurs. Neutrophils deploy various defense mechanisms to eradicate pathogens, including phagocytosis, degranulation, production of reactive oxygen species (ROS) via the NADPH oxidase complex, and release of neutrophil extracellular traps (NETs) as a suicidal mechanism to trap and kill pathogens. Our investigations center on the regulation of the CD11b/CD18 integrin and its downstream signaling pathways, including the identification of interacting proteins such as SKAP2, to elucidate the molecular mechanisms underpinning neutrophil anti-tumor responses. Moreover, we explore strategies to enhance neutrophil cytotoxicity towards cancer cells by targeting inhibitory immunoreceptor interactions, such as the CD47-SIRPα and SIGLEC-5/14 pathways, which hold promise for improving antibody-dependent cellular cytotoxicity (ADCC). We also examine tumor cell evasion mechanisms, exemplified by resistance against neutrophil trogocytosis mediated by the exocyst complex, highlighting the intricate interplay between innate immunity and cancer cell survival. These findings underscore the critical role of CD11b/CD18 in modulating neutrophil effector functions and offer novel insights into enhancing anti-tumor immune responses and developing potential therapeutic strategies in cancer treatment.