Identifying and engaging a universal adjuvant for breaking macrophage immune tolerance in cancer

Project Summary/Abstract The ability of cancer cells to evade immunosurveillance is one of the hallmarks of cancer. Understanding the mechanisms by which T, B and NK cells detect and attack cancer cells and developing approaches to break tumor immune tolerance have revolutionized the treatment of various human cancers. Macrophages are the

major components of primary tumors and metastatic sites, and emerging studies have demonstrated that the escape from macrophage immunosurveillance is a critical immune evasion mechanism of cancer cells. Recent paradigm-shifting discoveries have begun to reveal that inducing macrophage-mediated cancer cell recognition

and phagocytosis, a process termed programmed cell removal (PrCR), is crucial to tumor surveillance and elimination. A “don’t eat me” signal CD47 has been identified to be upregulated on a variety of malignant hematopoietic and solid tumor cells, and blockade of CD47 enables the susceptibility of cancer cells to PrCR.

Recent progress in clinical trials demonstrated significant therapeutic potential of restoring PrCR as a promising cancer immunotherapy. While inducing PrCR holds considerable promise in treating multiple types of cancers, its underlying mechanisms remain unclear, which have hindered the development of PrCR-based therapy to

achieve its maximal efficacy. The overall objective of this research proposal is to develop strategies to promote macrophage-mediated cancer surveillance and elimination by breaking macrophage tolerance, and to determine the efficacy and mechanisms of such strategies in PrCR-based cancer immunotherapy. The proposed studies

focus on identifying and engaging adjuvants to augment the anticancer efficacy of PrCR-based therapy, and dissecting the molecular mechanisms of PrCR activation and macrophage-cancer cell interaction. Aim1 is to examine the roles of PrCR adjuvants in enhancing the efficacy of CD47-blocking antibodies, determine to what

extent the adjuvants break macrophage immune tolerance to augment PrCR-based therapy, and decipher the composition and phenotype of tumor-associated macrophages upon the treatment of the adjuvants, with in vitro and in vivo preclinical cancer models. Aim2 is focused on understanding the molecular mechanisms of the

adjuvants in augmenting the efficacy of PrCR-based therapy, by identifying the molecular machinery involved in cancer cell phagocytosis and the function and regulation of PrCR immune checkpoints in mediating macrophage- cancer cell interaction. A combination of in vitro and in vivo cell biological, biochemical, bioinformatic, and

immunological methods will be used for the proposed studies. The investigation of the underlying mechanism of PrCR activation and regulation will enable a better understanding of the basic principles of cancer development and inspire the invention of more effective cancer immunotherapies. Successful completion of this study will lead

to the identification of novel functional components mediating cancer immune evasion and will immediately provide novel therapeutic opportunities for a variety of cancers.