Rehabilitating killers: leveraging immunomodulatory natural killer cell functions to orchestrate anti-tumor immunity

Abstract

Immunotherapies harness the immune system to kill cancer and have revolutionized cancer treatments. While durable immune responses against cancer rely on the adaptive arm of the immune system, it is the innate immune system that initiates and shapes its response. Seeking to better understand the immune features that support patient responses to immune checkpoint blockade (ICB) immunotherapies, previous work from our group identified a protective innate immune axis in the tumor microenvironment (TME), where natural killer (NK) cells support the maintenance of type one conventional dendritic cells (cDC1) through the production of the cDC1-formative growth factor Flt3L. The abundance of this NK cell–Flt3L–cDC1 axis correlates with increased overall survival and defines patient responsiveness to ICB therapy. These findings add to the growing body of literature emphasizing the important role NK cells play in orchestrating immune responses beyond cytotoxicity. Yet despite the clear clinical relevance, the mechanisms regulating NK cell production of Flt3L are currently unknown. To address this knowledge gap, my dissertation work investigates the molecular and cellular mechanisms that regulate Flt3L. Chapter 1 provides a detailed introduction into the role of the immune system in the cancer response, with particular attention given to NK cells and cDC1s. In Chapter 2, I describe a set of experiments that we performed to understand which signaling pathways in the tumor, and which subsets of NK cells, have a role in regulating Flt3L production and cDC1 abundance, and how this information can be used in the design of future immunotherapies. In Chapter 3, I present an investigation beyond the TME, where we explore a potential role for other cell populations in producing Flt3L, and supporting cDC1 abundance, in steady-state tissues. In Chapter 4, I discuss the findings of this dissertation work in the broader context of immunology and immunotherapies, and detail future work that will be crucial to more completely understand the mechanisms that support this protective immune axis.