CGEN009/JHU001 IS A NOVEL REGULATOR OF MYELOID CELL BIOLOGY IN HEALTH AND HUMAN DISEASE

Abstract

Immunotherapy represents the 4th pillar of cancer therapy and has the potential to result in a transformative treatment modality for patients for whom conventional therapies fail. This is based upon numerous results from clinical trials that demonstrate incredible efficacy for patients with diverse types of metastatic cancers. However, despite initial successes, these results are often limited to a handful of individuals with certain cancers, and immunotherapy has not panned out for individuals in many of the deadliest malignancies. As an alternative, we recognize the growing appreciation for the role of myeloid cells in cancer and their ability to impact tissue homeostasis. In this thesis, we provide a framework to challenge the current dogma in order to investigate the intersection between the immune system in cancer and predict important nodes whose perturbation may yield potential clinical breakthroughs. We identify a novel regulator of myeloid cell biology that is critical to tumor fitness and lipid metabolism. In chapter 1, we propose a novel paradigm that uses the perspective of evolution to understand the role of the immune system in cancer. In this manner, we are able to explain the successes and failures of immunotherapy, current challenges, and identify key features of future targets that may result in clinical benefits. In chapter 2, we delve into the biology of CGEN009/JHU001, a putative, previously uncharacterized protein of unknown function in mouse models. We show the effect of CGEN009/JHU001 on host homeostasis as well as it’s role in tumor biology that is dependent on myeloid cells. Finally, we identify key cell populations whose biology is dependent on the CGEN009/JHU001 path. In chapter 3, we investigate the biology of CGEN009/JHU001 in humans and find a unique transcriptional signature indicative of CGEN009/JHU001 signaling. We explore the presence of this transcriptional signature in a variety of disease states and reveal CGEN009/JHU001 as the upstream signal that induces the Trem2 myeloid signature. In chapter 4, we interrogate renal cell carcinoma clinical samples to identify a host of other myeloid-related proteins for future investigation. Overall, this work emphasizes the importance of myeloid cells in maintaining tissue homeostasis in health and disease