Current Understanding of the Mechanisms Underlying Immune Evasion From PD-1/PD-L1 Immune Checkpoint Blockade in Head and Neck Cancer

Abstract

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 Kok Immune Evasion From PD-1/PD-L1 Immunotherapy 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.

Using Gene Editing Approaches to Fine-Tune the Immune System

“…The serine/threonine kinase Cdk5 has been identified to regulate the PD-1/PD-L1 pathway. Its inhibition confers antitumor immunity due to interference with interferon regulatory factor 2 (IRF2) and interferon regulatory factor-binding protein 2 (IRF2BP2) (66,67). Consistent with this model, the depletion of CDK5 by shRNA leads to the hyperphosphorylation of IRFBP2, increased IRF2 expression, and lower PD-L1 levels (68,69).…”

Insights into Nanomedicine for Immunotherapeutics in Squamous Cell Carcinoma of the head and neck

“…Other strategies like adoptive cell transfer or anti-cancer vaccines are limited by reduced T cell activity, the development of autoimmune toxicity or weak immunogenicity [9,10]. Studies revealed that the heterogeneity in the spatial distribution of tumor-infiltrating lymphocytes (TILs), cancer stem cell (CSCs)-related immune invasion and the immunosuppressive microenvironment are the main factors contributing to the lower efficacy of ICB treatment at clinical stage [10,11]. In addition, similarly to the conventional cytotoxic chemotherapy drugs, immunotherapy is constrained by transport processes.…”

“…HNSCC tumors interfere with the immune system by employing many mechanisms that modulate functions of immune cells to develop immune evasion and immune escape (for more detailed information, please refer to reviews by Albers et al and Qian et al [18,19]). The potential mechanisms for the dysfunction of biological steps in immunity against cancer cells being responsible for the limited response to ICB treatment have been explored in HNSCC [11,[20][21][22][23][24][25][26]. Recently, three tumorimmunophenotypes and related molecular pathways have been recognized according to the spatial distribution of T cells within the tumor microenvironment [23].…”

A defucosylated anti-PD-L1 monoclonal antibody 13-mG2a-f exerts antitumor effects in mouse xenograft models of oral squamous cell carcinoma

“…PD-L1 has been utilized not only as a molecular marker of anti-PD-1 therapy, but also as a molecular target for antibody therapy. Anti-PD-L1 mAbs, such as atezolizumab, durvalumab, and avelumab has been used for patients with advanced head and neck squamous cell carcinoma (HNSCC) [ 24 ]. In 45%–87% of OSCC cases, cancer cells were PD-L1 positive, depending on the cut-off value for positivity and whether cytoplasmic staining was included as positive [ 24 ].…”

“…Anti-PD-L1 mAbs, such as atezolizumab, durvalumab, and avelumab has been used for patients with advanced head and neck squamous cell carcinoma (HNSCC) [ 24 ]. In 45%–87% of OSCC cases, cancer cells were PD-L1 positive, depending on the cut-off value for positivity and whether cytoplasmic staining was included as positive [ 24 ]. Anti-PD-L1 mAbs have been mainly used for PD1/PD-L1 blockade, but antitumor activities by antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) against oral cancers have not been investigated.…”