Immunotherapeutic strategies in head and neck cancer: challenges and opportunities

Abstract

HNSCC remains a substantial health issue, with treatment options including surgery, radiation, and platinum-based chemotherapy. Unfortunately, despite progress in research, only modest gains have been made in disease control, with existing treatments resulting in significant functional and quality-of-life issues. The introduction of immunotherapy in the treatment of HNSCC has resulted in some improvements in outlook for patients and is now standard of care for populations with both recurrent and metastatic disease. However, despite the early successes, responses to immune checkpoint inhibition (ICI) remain modest to low, approaching 14%-22% objective response rates. Challenges to the effectiveness of ICI and other immunotherapies are complex, including the diverse and dynamic molecular plasticity and heterogeneity of HNSCCs; lack of immunogenic antigens; accumulated suppressive immune populations such as myeloid cells and dysfunctional T cells; nutrient depletion; and metabolic dysregulation in the HNSCC tumor microenvironment. In this Review, we explore the mechanisms responsible for immunotherapy resistance, dissect these challenges, and discuss potential opportunities for overcoming hurdles to the development of successful immunotherapy for HNSCC.

Figure 1. Mechanisms driving resistance to immune checkpoint blockade therapy in HNSCC.

The potential mechanisms driving resistance to antitumor immune responses are illustrated. Overcoming immune-suppressive populations including Tregs, Bregs, tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), myeloid-derived suppressor cells (MDSCs), and cancer-associated fibroblasts (CAFs), as well as immune plasticity, will be critical for enhancing the response to immunotherapy and antitumor immunity. Defining cell-intrinsic features of HPV-related and carcinogen-driven (e.g., smoking) HNSCC will also be fundamental for reducing their tumor-intrinsic immune-suppressive capacity and immune escape mechanisms. Dysfunctional T cells generated by chronic antigen stimulation or T cell senescence induced by the tumor metabolome, proteome, and chemokine/cytokine milieu also impair the effectiveness of the immune response in HNSCC. Inadequate T cell costimulation drives T cell anergy, further impairing this response. Less-well-understood mechanisms driven by metabolic dysregulation impact the antitumor immune response in the tumor microenvironment, for which further work is warranted.

Figure 2. Features driving distinct immune pathogenesis in HPV⁺ versus HPV^– HNSCC.

Unique etiologies of HNSCC drive differential immune responses and pathogenesis. HPV⁺ HNSCCs are driven by dominant viral antigens (e.g., E6/E7), altered immune checkpoint signaling, and diminished cytosolic DNA–sensing functionality resulting in high levels of T lymphocyte infiltrates and germinal center B cells. In comparison, carcinogen-driven HNSCCs harbor a myeloid-rich, immune-suppressive tumor microenvironment driven by release of regulatory signaling molecules, genomic heterogeneity, and a lack of highly immunogenic neoepitopes. In HPV⁺ HNSCCs, viral oncoproteins promote loss of tumor suppressor gene expression and viral protein–mediated impairment of immunogenicity and antigen presentation. In HPV^– HNSCCs, carcinogens such as those found in tobacco smoke impair CD8⁺ T cell function. Collectively, these differences are associated with generally better survival outcomes in HPV⁺ HNSCC compared with HPV^– HNSCC. cDC2, type 2 conventional DCs.

Figure 3. Novel strategies for overcoming immunotherapy resistance in HNSCC.

(A) ICI can be enhanced by decreasing inhibitory T cell receptor signaling, reinvigorating dysfunctional T cells, and modulating metabolic pathways in cancer cells and suppressive immune populations. Neoadjuvant ICI can increase the antitumor immune response and debulk tumors prior to ablative surgery or cytotoxic therapy. Combining cytotoxic therapies with immunotherapy may also improve the antitumor immune response via dendritic cell activation and T cell priming, activation of pro-death signaling in tumor cells, and release of DAMPs. (B) Reversing T cell senescence may also be accomplished through MAPK pathway inhibition, lipid metabolism modulation, and DNA damage blockade. Inhibiting the ability of cancer cells and Tregs to induce T cell senescence offers a novel opportunity for increasing ICI responses. (C) Metabolic reprogramming of tumor cells and Tregs also provides novel strategies for HNSCC treatment. (D) Targeting suppressive immune and stromal populations will be critical for altering the overall balance of cytotoxic/effector to regulatory responses in the TME.