Starting in 2014, large phase III clinical trials began to disclose the study results of using programmed death (PD)-1
immune checkpoint inhibitors (ICIs) (
pembrolizumab,
nivolumab) and PD-
ligand (L)1 (
atezolizumab,
durvalumab,
avelumab) ICIs
immunotherapy in patients with advanced
head and neck squamous cell carcinoma (
HNSCC). In the recurrent and metastatic (R/M),
cisplatin-refractory setting,
nivolumab achieved a 2.2-fold increase of the median 1-year overall survival as compared with investigators' choice of salvage
chemotherapy (36.0 vs. 16.6%). A paradigm shift to the winning regimen,
pembrolizumab combined with
platinum and infusional
fluorouracil, has outperformed the past gold standard of
cetuximab-based
platinum and
fluorouracil combination in terms of overall survival (median, 13.6 vs. 10.1 mo) when administered as the first-line treatment for R/M
HNSCC. Nevertheless, many patients still did not respond to the PD-1/PD-L1 checkpoint inhibitor treatment, indicating innate, adapted, or quickly acquired resistance to the
immunotherapy. The mechanisms of resistance to ICIs targeting the PD-1/PD-L1 signaling pathway in the context of
HNSCC are the focus of this review. The past 5 years have seen improved understanding of the mechanisms underlying checkpoint inhibition resistance in
tumor cells, such as:
tumor cell adaption with malfunction of the
antigen-presenting machinery via class I
human leukocyte antigen (HLA), reintroduction of
cyclin D-
cyclin-dependent kinase (CDK) 4 complex to cell cycles, enrichment of CD44+
cancer stem-like cells, or development of inactivating mutation in IKZF1 gene; impairment of T-cell functions and proliferation through mutations in the
interferon-γ-regulating genes, suppression of the stimulator of
interferon genes (
STING) pathway, or resulted from constitutional nutritional
iron deficiency state; metabolic reprogramming by
cancer cells with changes in metabolites such as
GTP cyclohydrolase 1,
tetrahydrobiopterin,
kynurenine,
indoleamine 2,3-dioxygenase, and
arginase 1; defective dendritic cells, CD-69 sufficient state; and the upregulation or activation of the alternative immune checkpoints, including lymphocyte activation gene-3 (LAG3), T-cell
immunoglobulin and ITIM domain (TIGIT)/CD155 pathway, T-cell
immunoglobulin mucin-3 (TIM-3), and V domain-containing Ig suppressor of T-cell activation (VISTA). Several potential
biomarkers or biosignatures, which could predict the response or resistance to the PD-1/PD-L1 checkpoint
immunotherapy, are also discussed.