Coordinated Roles of T Cells and Natural Killer Cells in Tumor Immunity

Abstract:

Both adaptive immune cells, particularly T cells, and innate lymphoid cells, such as Natural Killer (NK) cells, play critical yet complementary roles in tumor immunity. While T cells mediate antigen-specific cytotoxic responses, NK cells provide rapid, innate recognition and elimination of transformed cells, and their interplay can significantly enhance antitumor immunity, offering potential improvements in immunotherapeutic efficacy. Recent studies indicate that NK cells are essential for recruiting type 1 conventional dendritic cells (cDC1) into the tumor microenvironment, which in turn promotes the activation and expansion of tumor-specific CD8+ T cells. Conversely, activated T cells secrete interleukin-2 (IL-2), a cytokine crucial for NK cell proliferation, survival, and cytotoxic function, establishing a positive feedback loop that amplifies immune responses against malignancies. Tumors, however, exploit immune evasion mechanisms, including modulation of the activating receptor NKG2D and its ligands MICA and MICB, to escape detection by both NK and T cells. Furthermore, these lymphocytes share important inhibitory and activating receptor pairs, such as CD161-CLEC2D, TIGIT-CD155, and NKG2A/CD94-HLA-E, which regulate cytotoxic potential and maintain immune homeostasis. Targeting these shared checkpoints or modulating receptor-ligand interactions represents a promising strategy to overcome tumor immune evasion. By elucidating the coordinated actions of NK and T cells and their shared regulatory pathways, novel immunotherapeutic approaches can be developed to enhance antitumor responses, improve treatment efficacy, and ultimately improve clinical outcomes for cancer patients.