Overcoming Resistance to Immune Checkpoint Inhibitors in Head and Neck Squamous Cell Carcinomas

Abstract

Preclinical data suggest that head and neck squamous cell carcinomas (HNSCC) may evade immune surveillance and induce immunosuppression. One mechanism of immune evasion involves the expression of programmed death ligand-1 (PD-L1) in tumor and immune cells, which is, to date, the only biomarker routinely used in clinical practice to select patients with advanced HNSCCs more likely to benefit from anti-PD-1 therapy. Nonetheless, PD-L1 expression alone incompletely captures the degree of sensitivity of HNSCCs to PD-1 inhibitors. Most patients exposed to anti-PD-1 antibodies do not respond to therapy, suggesting the existence of mechanisms of de novo resistance to immunotherapy. Furthermore, patients that initially respond to PD-1 inhibitors will eventually develop acquired resistance to immunotherapy through mechanisms that have not yet been completely elucidated. In this article, we will provide an overview of the immune landscape of HNSCCs. We will briefly describe the clinical activity of inhibitors of the PD-1/PD-L1 axis in this disease, as well as biomarkers of benefit from these agents that have been identified so far. We will review pre-clinical and clinical work in cancers in general, and in HNSCCs specifically, that have characterized the mechanisms of de novo and acquired resistance to immunotherapy. Lastly, we will provide insights into novel strategies under investigation to overcome resistance to immune checkpoint inhibitors.

Combination of Tumor Mutational Burden and Specific Gene Mutations Stratifies Outcome to Immunotherapy Across Recurrent and Metastatic Head and Neck Squamous Cell Carcinoma

“…However, the significance of TMB stratification in non-ICI cohorts of HNSCC was still uncertain. Although current evidence suggests that TMB is associated with increased efficacy of ICIs ( Chen et al, 2020 ; Sha et al, 2020 ), the underlying mechanism linking TMB to immunotherapy benefits is not fully understood ( Dos Santos et al, 2021 ). In addition, some studies have suggested that TMB is only useful for predicting the clinical response of some cancer patients (those with endometrial cancer, colorectal cancer, melanoma, lung adenocarcinoma, etc.)…”

Current and Future Biomarkers for Immune Checkpoint Inhibitors in Head and Neck Squamous Cell Carcinoma

“…Hanna et al reported a higher frequency of frameshift events in ICI responders compared to non-responders in patients with HNSCC [ 66 ]. Immune cell infiltration into the tumor microenvironment has also shown prognostic implications [ 67 , 68 ]. Analysis of the levels of CD4+ helper T cells, CD8+ cytotoxic T cells, and FoxP3+ regulatory T cells demonstrated an association of higher tumor-infiltrating lymphocytes (TILs) with improved OS and disease-specific survival even after controlling for other variables.…”

TMEM16A as a potential treatment target for head and neck cancer

“…However, PD-L1 expression alone did not completely capture the sensitivity of HNSCCs to PD-1 inhibitors. Furthermore, most patients who initially respond to PD-1 inhibitors eventually develop acquired resistance to immunotherapy through mechanisms that have not yet been completely understood [ 136 ].…”