Fig. 3 |. Increasing cellular interactions with tertiary lymphoid structures in the HNSCC TME for maximal humoral and cellular immunity.

Tertiary lymphoid structures (TLS) form within the tumour or surrounding the tumour stroma in patients with head and neck squamous cell carcinoma (HNSCC)^17,78,84. TLS vary in size and cell composition in patients, but an increased presence of TLS correlates with improved survival and reduced risk of recurrence in both human papillomavirus (HPV)-positive and HPV-negative HNSCC¹⁷. Within TLS, B cells co-localize with T follicular helper (T_FH) cells and receive activation signals via CD40, inducible T cell co-stimulator ligand (ICOSL) and major histocompatibility complex class II (MHC-II) engagement^17,29,84. Activation of B cells via T_FH cells leads to germinal centre formation, which is regulated by transcription factor B cell lymphoma 6 (BCL6) and marked by surface expression of semaphorin 4A (SEMA4A) on germinal centre B cells^17,165. Intratumoural germinal centre B cells in HPV-positive HNSCC have three distinct cell states: dark zone (DZ), light zone (LZ) and transitional (T), marked by unique patterns of gene expression that are important for the selection and maturation of B cells¹⁷. Formation of germinal centres within TLS is an independent predictor of superior progression-free survival in HNSCC¹⁷. As a result of successful germinal centre formation in HPV-positive HNSCC, germinal centres produce terminally differentiated somatic hypermutated antibody-secreting cells (ASCs) that have undergone immunoglobulin class-switching to an IgG1 isotype⁸². IgG1⁺ ASCs in patients with HPV-positive disease recognize HPV viral proteins E6, E7 and E2 (ref.⁸²). Antibodies directed at tumour-associated antigens (TAAs) have also been detected in the serum of patients with HPV-positive and HPV-negative HNSCC⁷⁸. Activated B cells might also provide co-stimulatory signals to CD8⁺ T cells, resulting in their expansion and survival in HNSCC tumours^81,84. Co-localization of B cells with CD8⁺ T cells is associated with favourable outcomes in HNSCC^81,84. Together, these features provide a new targetable axis for future immunotherapies, which should be directed at enhancing TLS formation, maturation of B cells and increasing B–T cell interactions within the TME of HNSCC. BCR, B cell receptor; fDC, follicular dendritic cell; ICOS, inducible T cell co-stimulator; TCR, T cell receptor.