Sunday, April 28, 2024
4/28/2024
Project Summary/Abstract Recent breakthroughs in tumor immunology led to the development of cancer immunotherapies which have been successfully applied to a range of human cancers. Among the immune cellularity in the tumor microenvironment, tumor-associated macrophages (TAMs) are often the most abundant immune cells and play critical roles in tumor immunosurveillance. Recent progress demonstrates that cancer cells upregulate anti-phagocytic “don’t eat me” signals as self-protective mechanisms against macrophage surveillance. When these signals are blocked, macrophages are capable of eliminating various malignant hematopoietic and solid tumor cells through cellular phagocytosis. Inducing cancer cell phagocytosis demonstrates significant anticancer effects and therapeutic potential in preclinical models and recent clinical trials. Tyrosine phosphorylation and dephosphorylation, mediated by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), is an essential mechanism underlying signal transduction involved in multiple critical biological functions including the regulation of immune responses. PTPs such as SHP1/SHP2 have been shown to be involved in the inhibitory signaling in macrophages and T cells for deactivating immune activities. Despite its importance, however, the underlying molecular mechanisms of macrophage-mediated cancer cell phagocytosis are still unclear, and the critical components mediating this process in addition to cell surface receptors have mainly remained unidentified. In this proposal, we are focusing on the functions and roles of PTPs in macrophage immunosurveillance. Through a CRISPR-based loss-of-function screening in macrophages, we have identified non-receptor PTP candidates that negatively regulate phagocytosis. When their expression is suppressed, the phagocytic ability of macrophages toward cancer cells is significantly enhanced. Our central hypothesis is that such PTPs function as inhibitory regulators of macrophage-mediated cancer cell phagocytosis, and thus their inhibition can promote the efficacy of macrophage phagocytosis-based cancer immunotherapy. In this proposal, we will first investigate to what extent the deficiency of inhibitory PTPs in macrophages promotes the efficacy of cancer cell phagocytosis with multiple preclinical models. Second, we will dissect the molecular mechanism of how deficiency of PTPs in macrophages augments cancer cell phagocytosis. Finally, we will examine the anticancer efficacy of suppressing PTPs in macrophages with in vivo cancer models. The completion of this study will identify and establish the roles of new regulators of cancer cell phagocytosis and inspire the development of new therapeutic strategies to enhance the efficacy of macrophage-based cancer immunotherapy.
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