Examining the immunomodulatory role of the CD47 in infectious diseases

CD47 is an important marker of self, functioning as a "don't eat me" signal to the innate immune system. Normal upregulation of CD47 serves to protect cells from phagocytosis during cellular stress. However, cancer cells aberrantly upregulate CD47 expression in order to evade immune recognition. High expression of CD47 has been demonstrated in hematologic cancers, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), non-Hodgkin's lymphoma (NHL), myeloma, and myelodysplastic syndromes; and solid tumor cancers, including ovarian cancer, breast cancer, bladder cancer, colon cancer, prostate cancer, hepatocellular carcinoma, pancreatic neuroendocrine tumors, small lung cell cancer, glioblastoma, and leiomyosarcoma. Therapeutic blockade of CD47 expression promotes innate immune cell phagocytosis of all of these cancers in preclinical models. Furthermore, therapeutic blockade of CD47 in preclinical in vivo tumor models was associated with reduced primary tumor burden and reduced metastasis. CD47 blockade is a broad and effective immunotherapy against so many distinct cancers because, although it does not specifically target cancer cells, CD47 upregulation is highly conserved as an immune evasion mechanism in most cancers. Thus, blockade of CD47 expression on cancer cells permits immune recognition of prophagocytic signals, which promotes cellular clearance by the innate immune system. In addition to the direct effect of CD47 blockade on innate immune cell phagocytosis, there is also evidence to support indirect effects of CD47 blockade on the adaptive immune system. Phagocytosis of cancer cell targets by antigen-presenting cells (APCs) leads to major histocompatibility complex (MHC) processing and presentation of cancer neoantigens. CD47 blockade-induced phagocytosis of cancer cells by APCs has been demonstrated to increase tumor-specific T cell activation. Thus by engaging both the innate and adaptive immune systems CD47 blockade initiates an immediate clearance of cancer cells by phagocytosis as well as long term adaptive immune recognition through enhanced T cell priming. Recently published data from two phase I clinical trials, in non-Hodgkin's lymphoma and advanced solid cancers, have demonstrated tolerability and validity of this novel immunotherapeutic approach. Globally infectious diseases are a leading cause of death in both adults and children. HIV and malaria infections alone are responsible for the deaths of almost 2 million people each year. Accordingly, development of therapies to prevent, diagnose, and treat infectious diseases represent a major public health objective. Given the broad therapeutic potential of CD47 blockade as an innate immune checkpoint inhibitor, the major aims of this thesis were to: 1) Determine whether CD47 expression modulates immune responses to pathogen recognition during infections. 2) Test CD47 blockade in preclinical models of infectious diseases. This thesis will show that CD47 expression negatively regulates immune responses in a broad range of infectious diseases, including several viruses, bacteria, and parasites. To evaluate the therapeutic potential of CD47 blockade against pathogens, CD47 blockade was tested in preclinical models of malaria and HIV. Ultimately, this thesis demonstrates that CD47 blockade enhances immune responses to infection and reduces morbidity and mortality in models of two major infectious diseases. While this thesis focuses on malaria and HIV, upregulation of CD47 was observed in several other infection models and future work should continue to identify additional clinical indications of this novel immunotherapy.

Keywords: Stem Cell Biology and Regenerative Medicine.
Advisor: Weissman Irving L. 
Egan Elizabeth S. 
Majeti Ravindra
Palmer Theo 
Shizuru Judith Anne