Date of Award
Fall 2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Immunobiology
First Advisor
Iwasaki, Akiko
Abstract
Deciphering the Tumor Immune Interactome Cancerous transformations are initiated in normal healthy cells by oncogenic hits. Subsequent acquisition of somatic mutations over time results in the transformation of aberrant cells to cancerous outgrowth to eventual metastatic dissemination. Since the multistep process of oncogenesis does not exist in a vacuum, as these cells arise within the context of a tissue, how does host defenses interact with aberrant transformed cancerous cells? As early as 1909, Paul Ehrlich offered the first hypothesis of immune interaction with tumor cells, arguing that the immune cells can recognize and protect against cancer cells. Further developed by Lewis Thomas and Seth MacFarlane Burnett in the 1950s, the framework of immune surveillance was presented whereby effector immune cells actively patrol the body to identify and eradicate tumor cells. Specifically, certain oncogenic mutations result in immune sensitive neo-antigens that can elicit anti-tumor immunity. This, and future work, have provided the basis of immunotherapeutic intervention in cancer. However, not all cancers elicit an immune response and tumors still develop in the presence of an intact immune system. Indeed, those that do elicit an immune response are usually derived from ‘immunogenic’ oncogenic hits that are carcinogenic (inducing high mutational burden) or viral in nature. Additionally, tumors are ‘self’ and non-infectious in nature, so how does the immune system sense tumor cells? In fact, immune responses to cancer range from tumor supportive to agnostic to eliminating. How the immune system interacts with tumor cells and the consequences of those interactions remains to be fully elucidated. The work presented in this dissertation summarizes our investigation into how the immune system interacts with tumor microenvironment in the context of different tumors, metastasis, and during novel immunotherapeutic treatments. Using murine cancer models and synthetic biology, we interrogated different aspects of the tumor immune interactome in order to understand the rules of immune engagement with cancer. In chapter 1, we provide an overview of proposed frameworks describing immune engagement during oncogenesis, what remains to be elucidated, and provide a synopsis of research presented in this thesis. In chapter 2 we present the development and immunophenotyping of novel cytokine-based immunotherapy, decoy resistant IL-18 (DR-18); highlighting previously underappreciated immune mechanisms that are remodeled following cytokine-based immunotherapy. In chapter 3, we interrogate how metastatic disseminated cells are sensed by the immune system and probe how innate and adaptive immune cells coordinate distinct interactions within the tumor microenvironment. In chapter 4, we present the development of a novel synthetic cell tagging tool that can report when immune cells come in physical contact with tumors cells. We utilize this tool to discover and interrogate the tumor immune interactome during immunological refractory and sensitive tumors and during different treatment modalities. Finally, chapter 5 highlights the implications of our key findings and provides perspective on key questions of the tumor immune interactome that remain unanswered. In conclusion, the work presented here deciphers key features of how the immune system interact with the tumor microenvironment during oncogenesis, metastasis and therapeutic intervention. Additionally, it provides critical tools to further probe the rules of tumor engagement by the immune system. The insights and technologies provided here uncover novel biology and hypotheses that hopefully can be leveraged for the next generation of immunotherapeutic strategies targeting cancer.
Recommended Citation
Weizman, Orr-El, "Deciphering immune interactions in the tumor microenvironment" (2023). Yale Graduate School of Arts and Sciences Dissertations. 1196.
https://elischolar.library.yale.edu/gsas_dissertations/1196
