Programmed Cell Death-Ligand 1 in Head and Neck Squamous Cell Carcinoma: Molecular Insights, Preclinical and Clinical Data, and Therapies
Abstract
:1. Introduction
2. Materials and Methods
3. Results
3.1. Molecular Structure and Function
3.1.1. PD-1 and PD1-L1 Structures
3.1.2. PD-1/PD-L1 Interaction
3.1.3. Biological Role
3.2. PD-L1 Tumor Expression
3.2.1. Genetic Modifications
3.2.2. Inflammatory Signaling
3.2.3. Oncogenic Pathways
3.2.4. miRNA-Mediated Regulation
3.2.5. Protein Level Regulation
3.2.6. Mechanisms of PD-L1 Overexpression Observed in HNSCC
3.3. Immunotherapy in HNSCC
3.4. Immunotherapy Resistance Mechanisms in HNSCC
4. Discussion
4.1. Biomarkers of Immunotherapy Response in HNSCC
4.2. Future Perspectives in HNSCC
4.3. New Molecules in HNSCC
4.4. HNSCC Therapy
4.5. Adverse Events in HNSCC Immunotherapy
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Mechanism/Molecule | Mechanism of Action | Refs |
---|---|---|
Genetic modifications | ||
Amplification | Amplification and translocation of PD-L1 gene (9p24.1) | [2,52] |
Translocation | ||
JAK-2 | JAK-2 hyperexpression due to amplifications and/or translocation (9p) | [48,53] |
miRNAs | 3′UTR binding | [2,49] |
Inflammatory signaling | ||
IFN-γ | IFN-γ activates JAK-STAT pathway (especially STAT1), causing the expression of IRFs | [53,54,55] |
LPS | LPS activates TLR4, which activates NF-κB. The latter increases type I interferons expression | [56,57] |
IL-17, IL-10, TNF-α, IL-4, IL-1b, IL-6, IL-27 | Inflammatory factors that enhance PD-L1 expression. | [58,59,60,61,62] |
Oncogenic pathways | ||
MYC | MYC interacts with the PD-L1 promoter which causes an increase in gene transcription | [63] |
HIF-1a, HIF-2a | HIF-1a and HIF-2a interact with HRE and activate the PD-L1 promoter | [64,65,66,67] |
STAT3 | STAT3 acts on PD-L1 promoter increasing his expression | [68,69] |
NF-κB | NF-κB p65 (RELA) subunit binds PD-L1 promoter and increases his expression | [70,71] |
CDK5 | CDK5 destabilizes IRF2-inducing PD-L1 expression | [72] |
AKT-mTOR cascade | PI3K activates AKT-mTOR cascade, that cascade increases PD-L1 expression | [73,74,75,76] |
RAS GTPase and/or BRAF tyrosine kinase activity | Increase in PD-L1 expression | [77,78] |
K-RAS, EGFR, ALK | K-RAS induces PD-L1 expression. EGFR acts through mTOR and ERK-dependent mechanisms. ALK uses STAT3 and MEK-ERK. | [79,80,81,82] |
miRNA-mediated regulation | ||
miR-513, -155, -34a, 142-5p, -93, -106b, -138-5p, -217 (laryngeal cancer), -200, -152, -570, -17-5p, -15a, -193a, -16 and -197 | PD-L1 suppressors | [79,80,81,82,83,84,85,86,87,88,89,90,91,92] |
miR-20, -21 and -16 | PD-L1 enhancers | [83] |
Protein level regulation | ||
CMTM6 and 4 | CMTM6 and 4 bind PD-L1 and prevent ubiquitination and lysosomal degradation. | [2,84,85] |
D-CDK4 (loss of function) | D-CDK4 phosphorylates SPOP and elicits the ubiquitination and degradation of PD-L1 | [86] |
NF-κB | NF-κB removes ubiquitin chains via CSN5 | [87] |
Molecule | Mechanism of Action | References |
---|---|---|
β2M mutations | Component of the MHC Class I heavy chain, his mutation hesitates in reduction of T cell recognizant of cancer cells | [54,55] |
IKZF1 | Mutation that reduces the inflammatory infiltrate | [56,57] |
KDM5B | Suppresses STING, CXCL10 levels, CD8+ infiltrate | [128] |
Increase of CD44+ stem-like cells | CD44+ stem-like cells inhibit T-cells and enhance immunosuppressive T-reg cells | [8] |
CD69 sufficient state | T-cells exhaustion | [130,131] |
GCP1 | Inhibition causes T-cells maturation prevention | |
BH4 | Reduction of BH4 inhibited by kineurine T-cells inhibiting | |
IDO1 | Increase of IDO1 reduces T-cells and inflammatory cells proliferation | [132] |
Arg-1 | Arg-1 increase expression leads to greater degradation of L-arginine, a key nutrient for lymphocytes | [133,134] |
TGF-β | Decrease dendritic cells in drainage lymph nodes and CD8+ cells. | [135,136,137,138] |
CD38, CD39 | CD8+ cells inhibition via adenosine receptor | [139,140] |
PMN-MDSC | PMN-MDSC activates the nitric oxide pathway which inhibits the proliferation and function of T-cells | [140,141,142,143] |
NRLP3 | NRLP3 activation increases MDSCs, T-regs, and TAMs, and reduces IL-1 β | [144] |
STAT-pathway and cytokines | Alteration of STAT-pathway leads to a dendritic cell loss of function | [131,145,146] |
LAG3, pathway of T-cell immunoglobulin, ITIM domain, TIM-3, VISTA | Alternative immune checkpoint | [8,147,148,149,150,151,152,153] |
ATRA and IFB-β | ATRA and IFB-β increase CD38 production via CD30-CD203a-CD73 axis. CD38 transforms NAD+ and NADP+ into cyclic ribose ADP (zADPR), NAADP, and ADPR, which act on calcium signaling | [8,142,143,150,154,155] |
CD73 | dephosphorylates extracellular AMP which leads to the production of adenosine. Adenosine binds to the A2a and A2b receptors of T and NK lymphocytes, neutrophils, dendritic cells, and macrophages with an immunosuppressive action | [139,140,141,155,156,157] |
HLA, β-2-macroglobulin and TRAF3 mutation | common in HPV+ HNSCC, whereas they are found in less than 10% of HPV− cancers. HPV antigens also enhance cytotoxic T-lymphocytes dysregulation. | [126] |
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Meliante, P.G.; Barbato, C.; Zoccali, F.; Ralli, M.; Greco, A.; de Vincentiis, M.; Colizza, A.; Petrella, C.; Ferraguti, G.; Minni, A.; et al. Programmed Cell Death-Ligand 1 in Head and Neck Squamous Cell Carcinoma: Molecular Insights, Preclinical and Clinical Data, and Therapies. Int. J. Mol. Sci. 2022, 23, 15384. https://doi.org/10.3390/ijms232315384
Meliante PG, Barbato C, Zoccali F, Ralli M, Greco A, de Vincentiis M, Colizza A, Petrella C, Ferraguti G, Minni A, et al. Programmed Cell Death-Ligand 1 in Head and Neck Squamous Cell Carcinoma: Molecular Insights, Preclinical and Clinical Data, and Therapies. International Journal of Molecular Sciences. 2022; 23(23):15384. https://doi.org/10.3390/ijms232315384
Chicago/Turabian StyleMeliante, Piero Giuseppe, Christian Barbato, Federica Zoccali, Massimo Ralli, Antonio Greco, Marco de Vincentiis, Andrea Colizza, Carla Petrella, Giampiero Ferraguti, Antonio Minni, and et al. 2022. "Programmed Cell Death-Ligand 1 in Head and Neck Squamous Cell Carcinoma: Molecular Insights, Preclinical and Clinical Data, and Therapies" International Journal of Molecular Sciences 23, no. 23: 15384. https://doi.org/10.3390/ijms232315384