Enhancing Anti-Cancer Properties of Human Natural Killer Cells

Abstract

Immunotherapy has revolutionized cancer treatment. Certain immunotherapies, such as immune checkpoint inhibitors and CAR-T cell therapy, provide long lasting remissions. Unfortunately, the majority of tumors are unresponsive to immunotherapy and tumors that initially respond frequently develop resistance. In order to improve patient clinical outcomes a greater understanding of anti-tumor immunology is required to broaden and refine immunotherapy treatment. While there are two types of cytotoxic lymphocytes that kill malignant cells, CD8+ T cells and natural killer (NK) cells, NK cells are under-studied in comparison to CD8+ T cells. In this dissertation, I explore multiple ways to enhance NK cell anti-cancer properties.

In cancer, patients with high tumoral NK cell content and activation have improved survival and response to immunotherapy. Because of this, NK cells are emerging as major targets to promote cancer immunotherapy. Current NK-focused immunotherapy approaches include autologous or allogenic NK cell transfer, CAR-NK cells, NK immune checkpoint inhibitors, bi- or tri-specific killer engagers (BiKEs and TriKES), and cytokine super-agonists. An impediment to all these therapies is inadequate NK cell honing to and/or infiltration into solid tumors. The first part of this dissertation describes approaches to enhance NK cell tumor honing and infiltration, either through pharmacologic means or by genetic engineering. Specifically, I detail 1) that NK cells express fibroblast activation protein (FAP) which regulates NK cell tumor infiltration (chapters 1, 2, 4 and 5) and 2) how a dipeptidyl peptidase inhibitor, which inhibits FAP and other members of the dipeptidyl peptidase family, enhances NK cell tumor infiltration and increases anti-PD-1 efficacy (chapter 3).

Once NK cells enter the tumor milieu, they can become exhausted, limiting their anti-tumor potential. NK cell exhaustion is marked by upregulation of immune checkpoints. While PD-1 and CTLA-4 are immune checkpoints expressed by exhausted T cells, their expression and functionality in NK cells is controversial. In chapter 6, I demonstrate human NK cells express CTLA-4 and suggest anti-CTLA-4 immune checkpoint therapy may restore NK cell function leading to tumoral NK cell activation.

In sum, this dissertation describes multiple novel approaches to altering NK cell biology to enhance their anti-tumor activity and potentially improve patient outcomes.