Clinical and basic science aspects of innate lymphoid cells as novel immunotherapeutic targets in cancer treatment.

Immunotherapy has revolutionised cancer treatment over the past decade, demonstrating remarkable efficacy across a broad range of cancer types. However, not all patients or cancer types respond to contemporary clinically-utilised immunotherapeutic strategies, which largely focus on harnessing adaptive immune T cells for cancer treatment. Accordingly, it is increasingly recognised that upstream innate immune pathways, which govern and orchestrate the downstream adaptive immune response, may prove critical in overcoming cancer immunotherapeutic resistance. Innate lymphoid cells (ILCs) are the most recently discovered major innate immune cell population. They have overarching roles in homeostasis and orchestrating protective immunity against pathogens. As innate immune counterparts of adaptive immune T cells, ILCs exert effector functions through the secretion of cytokines and direct cell-to-cell contact, with broad influence on the overall immune response. Importantly, dysregulation of ILC subsets have been associated with a range of diseases, including immunodeficiency disorders, allergy, autoimmunity, and more recently, cancer. ILCs may either promote or inhibit cancer initiation and progression depending on the cancer type and the specific ILC subsets involved. Critically, therapeutic targeting of ILCs and their associated cytokines shows promise against a wide range of cancer types in both preclinical models and early phase oncology clinical trials. This chapter provides a comprehensive overview of the current understanding of ILC subsets and the associated cytokines they produce in cancer pathogenesis, with specific focus on how these innate pathways are, or can be targeted, therapeutically to overcome therapeutic resistance and ultimately improve patient care.