Head and Neck Carcinoma Immunotherapy: Facts and Hopes

Abstract

Cancer of the head and neck (HNC) is a heterogeneous disease of the upper aerodigestive tract, encompassing distinct histologic types, different anatomic sites, and human papillomavirus (HPV)-positive as well as HPV-negative cancers. Advanced/recurrent HNCs have poor prognosis with low survival rates. Tumor-mediated inhibition of antitumor immune responses and a high mutational burden are common features of HNCs. Both are responsible for the successful escape of these tumors from the host immune system. HNCs evolve numerous mechanisms of evasion from immune destruction. These mechanisms are linked to genetic aberrations, so that HNCs with a high mutational load are also highly immunosuppressive. The tumor microenvironment of these cancers is populated by immune cells that are dysfunctional, inhibitory cytokines, and exosomes carrying suppressive ligands. Dysfunctional immune cells in patients with recurrent/metastatic HNC can be made effective by the delivery of immunotherapies in combination with conventional treatments. With many promising immune-based strategies available, the future of immune therapies in HNC is encouraging, especially as methods for genetic profiling and mapping the immune landscape of the tumor are being integrated into a personalized approach. Efficiency of immune therapies is expected to rapidly improve with the possibility for patients' selection based on personal immunogenomic profiles. Noninvasive biomarkers of response to therapy will be emerging as a better understanding of the various molecular signals co-opted by the tumors is gained. The emerging role of immunotherapy as a potentially beneficial addition to standard treatments for recurrent/metastatic HNC offers hope to the patients for whom no other therapeutic options exist. Clin Cancer Res; 24(1); 6-13. ©2017 AACR.

Figure 1

The TME of HNCs is rich in lymph nodes (LNs) which drain the tumor but also serve as key immune organs for T cell differentiation, maturation and interaction with DCs presenting tumor antigens. The milieu of the tumor-draining LN is saturated by tumor-derived inhibitory factors (TGF-β, IL-10, IL-6, PD-L1, JAG-1) and is deficient in IL-2 and IFNγ. In this cytokine milieu, T cells are polarized to differentiate into Treg or Th17 lineages and away from the IFNγ-producing Th1 effector cells phenotype. As a result, tumor-infiltrating lymphocytes (TIL) are enriched in Treg and pro-inflammatory Th17 cells but lacking in Th1 anti-tumor effector cells. The skewed differentiation of T cells in the TME results in dysregulation of anti-tumor immunity. Tbet, RORγt and FOXP3 are transcription factors that determine T cell lineages. Tumor-derived exosomes carrying immunosuppressive cargoes contribute to the inhibitory environment.

Figure 2

The rationale for combination of immunotherapy with conventional anti-tumor therapy. The conventional therapy for HNC can (1) induce immunogenic death of tumor cells and release tumor antigens that can be successfully processed and presented to T cells by DCs; (2) eliminate or decrease the numbers of Treg or MDSC which interfere with anti-tumor activity of T cells; and (3) sensitize tumor cells to lysis by immune effector cells. The subsequent blockade of immune checkpoints (CTLA-4, PD-1) allows tumor-reactive T cells to expand and exercise anti-tumor activities. This requires further modification of the TME and the delivery of cytokines that are necessary for expansion of tumor-reactive T cells and for the maintenance of their anti-tumor functions. Ultimately, these CTLs will be responsible for elimination of residual tumor cells. Conventional therapies not only eliminate tumor cells, providing a pool of antigens for presentation to T cells, but they also set the stage for immune cells rejuvenated by immune therapies, such as ICIs, to eliminate residual tumor cells.