Investigating functions of tumor-infiltrating natural killer cells in genetically-engineered mouse models of non-small cell lung cancer

Abstract

The immune system has long been hypothesized to play a role in restraining tumor growth, but compelling evidence for this role evaded scientists for the better part of a century. After many years of skepticism, the field of cancer immunology has recently undergone a major revolution. The success of modern immunotherapeutics has transformed the arenas of oncology and drug development. Large efforts are now focused on understanding the factors that dictate patient responses to immunotherapy, for the identification of possible points of intervention to expand the fraction of patients who benefit from therapy. The majority of approved immunotherapeutics directly target adaptive immune effectors. However, emerging evidence suggests that these treatments preferentially benefit patients with pre-existing immune responses against tumors, and patients who fail therapies often harbor tumors that are poorly infiltrated by adaptive immune cells. I have explored the role of an innate immune effector known for its capacity to kill tumor cells and its importance in stimulating and shaping adaptive immune responses, the natural killer (NK) cell. To this end, I developed a new system for assaying NK cell function in the context of established, autochthonous lung cancer, by engineering vectors for producing tumors with inducible NK cell activating ligands. Using this model, I have shown that NK cells in established tumors exhibit dysfunctional phenotypes, but their responses can be boosted by providing activating stimuli. Strikingly, stimulation of NK cells results in the recruitment of adaptive immune cells to tumors. By developing a next-generation model for inducing activating NK cell ligands in tumors engineered to express T cell antigens, I demonstrated that NK cell activation in immunogenic tumors results in effective immune responses that restrain tumor growth, highlighting the potential for cooperation between innate and adaptive arms of the immune system in anti-tumor immunity. Finally, I developed a novel immunotherapeutic molecule for stimulating NK cell responses against cancer cells. Bifunctional molecules are an emerging class of anti-cancer agents, designed to target immune effectors against tumors. I produced and performed initial functional testing on a bifunctional molecule that stimulates NK cell responses against tumors by 'decorating' the surface of cancer cells with activating NK cell ligands. I demonstrated that this bifunctional molecule induces NK cell cytotoxicity against tumor targets. Based on this work, we hypothesize that strategies for stimulating NK cells in tumors may enhance the efficacy of T cell-targeted therapies in the treatment of cancer.