Heterogeneity of the Head and Neck Squamous Cell Carcinoma Immune Landscape and Its Impact on Immunotherapy

Abstract

Head and neck squamous cell carcinomas (HNSCCs) are highly aggressive, multi-factorial tumors in the upper aerodigestive tract affecting more than half a million patients worldwide each year. Alcohol, tobacco, and human papillomavirus (HPV) infection are well known causative factors for HNSCCs. Current treatment options for HNSCCs are surgery, radiotherapy, chemotherapy, or combinatorial remedies. Over the past decade, despite the marked improvement in clinical outcome of many tumor types, the overall 5-year survival rate of HNSCCs remained ∼40-50% largely due to poor availability of effective therapeutic options for HNSCC patients with recurrent disease. Therefore, there is an urgent and unmet need for the identification of specific molecular signatures that better predict the clinical outcomes and markers that serve as better therapeutic targets. With recent technological advances in genomic and epigenetic analyses, our knowledge of HNSCC molecular characteristics and classification has been greatly enriched. Clinical and genomic meta-analysis of multicohort HNSCC gene expression profile has clearly demonstrated that HPV⁺ and HPV^- HNSCCs are not only derived from tissues of different anatomical regions, but also present with different mutation profiles, molecular characteristics, immune landscapes, and clinical prognosis. Here, we briefly review our current understanding of the biology, molecular profile, and immunological landscape of the HPV⁺ and HPV^- HNSCCs with an emphasis on the diversity and heterogeneity of HNSCC clinicopathology and therapeutic responses. After a review of recent advances and specific challenges for effective immunotherapy of HNSCCs, we then conclude with a discussion on the need to further enhance our understanding of the unique characteristics of HNSCC heterogeneity and the plasticity of immune landscape. Increased knowledge regarding the immunological characteristics of HPV⁺ and HPV^- HNSCCs would improve therapeutic targeting and immunotherapy strategies for different subtypes of HNSCCs.

Keywords: checkpoint blockade; head and neck squamous cell carcinomas; heterogeneity; immune landscape; immunosuppression; immunosurveillance; neoantigen.

FIGURE 1

Schematic illustration of the cellular and molecular processes associated with innate and adaptive immunity mediated pathogen and tumor elimination.

FIGURE 2

Schematic illustration of the co-stimulatory and co-inhibitory molecules involved in regulating T cell functional status of productive activation or tolerance/exhaustion.

FIGURE 3

Schematic illustration of three outcomes of tumor immunosurveillance. (A) Tumors are eliminated by productive antitumor immunity of activated T cells and/or innate immune cells in the dominantly immunostimulatory TME. (B) Co-existence of activated immune cells that kill some of the tumor cells and ignorant/tolerant immune cells resulting in the survival of residual tumors and an overall tumor “dormancy.” (C) In the immunosuppressive TME, tumors and pro-inflammatory myeloid-derived suppressor cells (MDSCs) induce T cell tolerance and prevent tumors being recognized by host immunity, thereby promoting tumor progression.