Fig. 2 |. New T cell targets in the HNSCC TME.

T cells are important in antitumour immunity, and human papillomavirus (HPV)-positive tumours generally show higher T cell infiltration and are associated with better outcomes than HPV-negative tumours^32–34. CD8⁺ T cells can directly lyse target cells by releasing granzymes and perforin in an antigen-directed manner. Chronic engagement with tumour antigens leads to a dysfunctional state characterized by high expression of immune-checkpoint receptors (PD1, T cell immunoglobulin and mucin domain 3 (TIM3), lymphocyte-activation protein 3 (LAG3) and CTLA4)^36–39. An HPV16-specific CD8⁺PD1⁺ T cell population in HPV-positive tumours contains a stem-like CD8⁺ T cell subset. These cells are capable of proliferating and differentiating into effector cells upon HPV peptide stimulation and represent a population of future therapeutic targets²⁸. CD4⁺ T lymphocytes recognize major histocompatibility complex (MHC) class II antigens and differentiate into different subtypes upon antigen stimulation. A higher number of T helper 1 (T_H1) and T_H17 cells are found in HPV-positive tumours than in HPV-negative tumours^48,49. T_H1 cells release IFNγ and TNF and promote MHC class I and II upregulation on cancer cells, facilitating tumour elimination^43,44. IL-17-releasing T_H17 cells are induced by IL-6, IL-23 and IL-1β produced by primary tumour cells^51,52. CXCR5⁺PD1⁺ICOS⁺CD40L⁺ T follicular helper (T_FH) cells produce CXCL13 and IL-21, recruiting B cells into the tumour microenvironment (TME)^56,57. T_FH cells are essential for B cell activation, maturation and tertiary lymphoid structure (TLS) formation in tumours, and their presence is associated with improved outcomes²⁹. T regulatory (T_reg) cells have an immunosuppressive role in the TME. T_reg cells can suppress effector cells through the release of IL-10, TGFβ and IL-35. High levels of CD25 on T_reg cells compete with effector cells for local IL-2, so that effector cells might not have enough IL-2 to survive and function^58–60. T_reg cells also express CD39 and CD73, which convert extracellular ATP to adenosine and impair effector T cell function^58,67. Co-expression of 4–1BB, GITR and neuropilin 1 (NRP1) on intratumoural T_reg cells demonstrated an enhanced suppression function^29,61,63. Immune-checkpoint receptors, such as TIM3 and CTLA4, are reportedly expressed by T_reg cells in head and neck squamous cell carcinoma (HNSCC). Both are highly expressed by intratumoural T_reg cells and able to suppress effector cell functions^21,22,63,64. Therapeutically targeting T_reg cells might help rejuvenate effector cell function. DC, dendritic cell; ICOS, inducible T cell co-stimulator; TCR, T cell receptor; TIGIT, T cell immunoreceptor with immunoglobulin and ITIM domains.