Table 3.
Mechanisms of immune escape that are implicated in HNSCC.
| Potential mechanisms | HPV+ or HPV- | Component in the immunity against cancer | References |
|---|---|---|---|
| TUMOR CELLS ADAPTION | |||
| Antigen presenting machinery (APM) via class I HLA | No data | Activated CD8+ immunologic pressure could induce transcriptional loss of HLA class one loci; deleterious alterations in JAK1/2 and β2-microglobulin. | (49–52) |
| Downregulation of the transporter associated with antigen processing (TAP)-1/2 heterodimer | APM component downregulated by the IFN-γ-phosphorylated STAT1-mediated signaling pathway; results in escaping recognition by tumor antigen-specific cytotoxic T lymphocytes. | (53, 54) | |
| JAK mutation | Both | Leads to loss of sensitivity to IFN-γ signals. | (35) |
| Cyclin D–CDK4 kinase re-introduction | No data | Destabilizes PD-L1 and controls the PD-L1 abundance in tumor cells. | (55) |
| Enrichment of CD44+ cancer stem-like cells | No data | Activates immunosuppressive network through cytokine release. | (54) |
| IKZF1-inactivating mutations | No data | Genomic alterations of the master regulator IKZF1 correlates with low immune recruitment. | (56) |
| IMPAIRED T-CELL FUNCTIONS AND PROLIFERATION | |||
| Nutritional iron deficiency state | Both | Affects T-cell proliferation | (57–59) |
| Mutations in interferon-γ-regulating genes | Both | Exhausted “Immune Class” enriched with M2 macrophages, WNT/TGF-β activation | (60, 61) |
| Suppression of stimulator of interferon genes (STING) pathway | HPV+ | Dampens the antitumor immune response. | (62) |
| Inhibition of STAT1 phosphorylation | Both | Enhanced T-cell exhaustion and accumulation of MDSCs | (63) |
| CHANGES IN METABOLITE- AND CYTOKINE-RICH TUMOR MICROENVIRONMENTS | |||
| Defective dendritic cells (DC) | Both | Defective cytokine- and STAT-mediated regulation of DC. | (64–66) |
| CD69-sufficient state | Both | Leads to effector T-cell exhaustion. | (67) |
| Genetic inactivation of GTP cyclohydrolase 1 (GCP1) | No data | Drastically impairs T-cell maturation. | (58) |
| Metabolite tetrahydrobiopterin (BH4) inhibited by kynurenine | No data | Will impair T cell function. | (58) |
| Indoleamine 2,3-dioxygenase-1 (IDO1); Tryptophan metabolite, kynurenine (Kyn) level | Both | IDO1 inhibits T cell proliferation, restricts tumor immune infiltration, and retards antitumor immune responses. Kyn released from ϕ, and myeloid cells activate T-reg cells. | (12, 68, 69) |
| Cancer-associated fibroblasts secrete TGF-β | Both | Results in restraining CD8+ T effector cells infiltrating into microenvironment. TGF-β1 also decreases the number of dendritic cells in the draining lymph nodes. |
(32, 70–73) |
| Arginase 1 expression on microenvironment myeloid cells | Both | Arg1 leads to L-arginine depletion depriving T cells and NK cells of essential nutrients required for proliferation. | (74) |
| CD38-upregulation | Both | CD38 inhibits CD8+ T-cell function via adenosine receptor signaling. | (75, 76) |
| Ectonucleotidases CD39/CD73 axis | Both | CD39 is considered a tumor-specific dysfunction marker. Tregs use the axis to diminish anti-cancer killing. | (76–79) |
| Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) activation | Both | Through the nitric oxide pathway, PMN-MDSCs impair proliferation and expression molecules in activated T cells. | (41) |
| Nucleotide-binding domain leucine-rich repeat and pyrin domain containing receptor 3 (NLRP3) inflammasome activation | Both | Leads to downstream interleukin (IL)-1β release. NLRP3 inflammasome/IL-1β axis increases MDSCs, Tregs and TAMs creating an immunosuppressive microenvironment. | (80) |
| ACTIVATION OF AND DEPENDENCE ON ALTERNATIVE IMMUNE CHECKPOINTS | |||
| Lymphocyte activation gene-3 (LAG3) (=CD223) upregulation | More in HPV+ | Induces a state of functional exhaustion in effector T-cells. | (81, 82) |
| T-cell immunoglobulin and ITIM domain (TIGIT)/CD155 pathway activation | Both | Augments TIGIT+ T-regs, a unique T-reg subset, leading to active suppression of anti-tumor immune response and T-cell exhaustion. | (82–85) |
| T-cell immunoglobulin mucin-3 (TIM-3) upregulation | Both | TIM-3 is considered a tumor-specific dysfunction marker. It dampens effector T-cell functions in the microenvironment. | (44, 48, 77, 86) |
| V domain-containing Ig suppressor of T-cell activation (VISTA) | Both | Leads to T-cell exhaustion and T-reg recruitment in the microenvironment. | (87, 88) |
Investigated mechanisms of acquired immune escape from PD-1/PD-L1 checkpoint blockade relevant to head and neck cancer.