Immune Checkpoints and Innate Lymphoid Cells—New Avenues for Cancer Immunotherapy

SIMPLE SUMMARY: Targeting the inhibitory receptors expressed by immune cells has revolutionized the clinical management of cancer patients. Initially developed to enhance T cell responses, recent investigations have demonstrated that innate lymphoid cells (ILC) also express many of these checkpoint molecules and could therefore be impacted by checkpoint blockade-based therapies. The diversity of the innate lymphoid cell family and their critical role in maintaining tissue homeostasis has drawn broad interest from the field to investigate their function in cancer. Here, we discuss recent findings highlighting the diversity of ILC in tissues and their capacity to migrate into organs upon inflammatory challenge. We further provide a comprehensive overview of the current knowledge on immune checkpoint (IC) expression on ILC, focusing on their therapeutic potential and capacity to modulate anti-tumor immune response. ABSTRACT: Immune checkpoints (IC) are broadly characterized as inhibitory pathways that tightly regulate the activation of the immune system. These molecular “brakes” are centrally involved in the maintenance of immune self-tolerance and represent a key mechanism in avoiding autoimmunity and tissue destruction. Antibody-based therapies target these inhibitory molecules on T cells to improve their cytotoxic function, with unprecedented clinical efficacies for a number of malignancies. Many of these ICs are also expressed on innate lymphoid cells (ILC), drawing interest from the field to understand their function, impact for anti-tumor immunity and potential for immunotherapy. In this review, we highlight ILC specificities at different tissue sites and their migration potential upon inflammatory challenge. We further summarize the current understanding of IC molecules on ILC and discuss potential strategies for ILC modulation as part of a greater anti-cancer armamentarium.