Head and neck cancer is one of the most prevalent cancers around the world. Head and neck squamous cell carcinoma (HNSCC) accounts for nearly 90% of head and neck cancer. In recent years, significant advances have been made in immunotherapy for HNSCC. Although some clinical trials targeting immune checkpoints have shown success, the molecular mechanism for regulation of programmed death 1 (PD-1) and its ligand (PD-L1) is partially understood. In an effort to explore the effect of activation of signal transducers and activators of transcriptions (STAT3) on PD-1/PD-L1, the expression and correlation between phosphorylation of STAT3 and PD-1/PD-L1 were determined with immunostaining of human and mouse HNSCC tissue sections. PD-1/PD-L1 overexpression was found to be significantly associated with p-STAT3 in human and mouse HNSCC. Targeting STAT3 by a small molecule effectively inhibited the expression of PD-L1 in the CAL27 cell line. Furthermore, we found that blockade of STAT3 signaling downregulated PD-1/PD-L1 in a Tgfbr1/Pten 2cKO HNSCC mouse model. These findings suggest that STAT3 signaling plays an important role in PD-1/PD-L1 regulation and the antitumor immune response of HNSCC.
BellmuntJPowlesTVogelzangNJ. 2017. A review on the evolution of PD-1/PD-L1 immunotherapy for bladder cancer: the future is now. Cancer Treat Rev. 54:58–67.
2.
BlackburnSDShinHHainingWNZouTWorkmanCJPolleyABettsMRFreemanGJVignaliDAWherryEJ. 2009. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol. 10(1):29–37.
3.
BrombergJDarnellJEJr.2000. The role of stats in transcriptional control and their impact on cellular function. Oncogene. 19(21):2468–2473.
4.
BuLLYuGTDengWWMaoLLiuJFMaSRFanTFHallBKulkarniABZhangWF. 2016. Targeting STAT3 signaling reduces immunosuppressive myeloid cells in head and neck squamous cell carcinoma. Oncoimmunology. 5(5):e1130206.
5.
BuLLZhaoZLLiuJFMaSRHuangCFLiuBZhangWFSunZJ. 2015. STAT3 blockade enhances the efficacy of conventional chemotherapeutic agents by eradicating head neck stemloid cancer cell. Oncotarget. 6(39):41944–41958.
6.
BuchbinderEIHodiFS. 2016. Melanoma in 2015: immune-checkpoint blockade—durable cancer control. Nat Rev Clin Oncol. 13(2):77–78.
7.
BudcziesJKlauschenFSinnBVGyorffyBSchmittWDDarb-EsfahaniSDenkertC. 2012. Cutoff Finder: a comprehensive and straightforward web application enabling rapid biomarker cutoff optimization. PLoS One. 7(12):e51862.
8.
ChakravartiNMyersJNAggarwalBB. 2006. Targeting constitutive and interleukin-6-inducible signal transducers and activators of transcription 3 pathway in head and neck squamous cell carcinoma cells by curcumin (diferuloylmethane). Int J Cancer. 119(6):1268–1275.
9.
ChangCHQiuJO’SullivanDBuckMDNoguchiTCurtisJDChenQGindinMGubinMMvan der WindtGJ. 2015. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell. 162(6):1229–1241.
10.
DaudAIWolchokJDRobertCHwuWJWeberJSRibasAHodiFSJoshuaAMKeffordRHerseyP. 2016. Programmed death-ligand 1 expression and response to the anti-programmed death 1 antibody pembrolizumab in melanoma. J Clin Oncol. 34(34):4102–4109.
11.
FerrisRL. 2015. Immunology and immunotherapy of head and neck cancer. J Clin Oncol. 33(29):3293–3304.
12.
FerrisRLBlumenscheinGJr.FayetteJGuigayJColevasADLicitraLHarringtonKKasperSVokesEEEvenC. 2016. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 375(19):1856–1867.
13.
FreemanGJLongAJIwaiYBourqueKChernovaTNishimuraHFitzLJMalenkovichNOkazakiTByrneMC. 2000. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 192(7):1027–1034.
14.
GaykalovaDAManolaJBOzawaHZizkovaVMortonKBishopJASharmaRZhangCMichailidiCConsidineM. 2015. NF-kappab and stat3 transcription factor signatures differentiate HPV-positive and HPV-negative head and neck squamous cell carcinoma. Int J Cancer. 137(8):1879–1889.
15.
GovenderUCorreBBourdacheYPellegriniSMichelF. 2017. Type I interferon-enhanced IL-10 expression in human CD4 T cells is regulated by STAT3, STAT2, and BATF transcription factors. J Leukoc Biol. 101(5):1181–1190.
16.
HongAMVilainRERomanesSYangJSmithEJonesDScolyerRASoon LeeCZhangMRoseB. 2016. PD-L1 expression in tonsillar cancer is associated with human papillomavirus positivity and improved survival: implications for anti-PD1 clinical trials. Oncotarget. 7(47):77010–77020.
17.
IsayevaTXuJRaginCDaiQCooperTCarrollWDayanDVeredMWenigBRosenthalE. 2015. The protective effect of p16(INK4a) in oral cavity carcinomas: P16(Ink4A) dampens tumor invasion-integrated analysis of expression and kinomics pathways. Mod Pathol. 28(5):631–653.
18.
JemalABrayFCenterMMFerlayJWardEFormanD. 2011. Global cancer statistics. CA Cancer J Clin. 61(2):69–90.
19.
JiangXZhouJGiobbie-HurderAWargoJHodiFS. 2013. The activation of MAPK in melanoma cells resistant to BRAF inhibition promotes PD-L1 expression that is reversible by MEK and PI3K inhibition. Clin Cancer Res. 19(3):598–609.
20.
Lo PrestiEToiaFOieniSBuccheriSTurdoAMangiapaneLRCampisiGCaputoVTodaroMStassiG. 2017. Squamous cell tumors recruit gammadelta T cells producing either IL17 or ifngamma depending on the tumor stage. Cancer Immunol Res. 5(5):397–407.
21.
MahoneyKMRennertPDFreemanGJ. 2015. Combination cancer immunotherapy and new immunomodulatory targets. Nat Rev Drug Discov. 14(8):561–584.
22.
MansfieldASAubryMCMoserJCHarringtonSMDroncaRSParkSSDongH. 2016. Temporal and spatial discordance of programmed cell death-ligand 1 expression and lymphocyte tumor infiltration between paired primary lesions and brain metastases in lung cancer. Ann Oncol. 27(10):1953–1958.
23.
MiklossyGHilliardTSTurksonJ. 2013. Therapeutic modulators of stat signalling for human diseases. Nat Rev Drug Discov. 12(8):611–629.
24.
MullenMGonzalez-PerezRR. 2016. Leptin-induced jak/stat signaling and cancer growth. Vaccines (Basel). 4(3):pii:E26.
25.
NishimuraHAgataYKawasakiASatoMImamuraSMinatoNYagitaHNakanoTHonjoT. 1996. Developmentally regulated expression of the PD-1 protein on the surface of double-negative (CD4-CD8-) thymocytes. Int Immunol. 8(5):773–780.
26.
OestreichKJYoonHAhmedRBossJM. 2008. NFATc1 regulates PD-1 expression upon T cell activation. J Immunol. 181(7):4832–4839.
27.
OkazakiTHonjoT. 2007. PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol. 19(7):813–824.
28.
PardollDM. 2012. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 12(4):252–264.
29.
SiddiqueeKZhangSGuidaWCBlaskovichMAGreedyBLawrenceHRYipMLJoveRMcLaughlinMMLawrenceNJ. 2007. Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity. Proc Natl Acad Sci U S A. 104(18):7391–7396.
30.
SullivanRJFlahertyKT. 2015. Immunotherapy: anti-PD-1 therapies-a new first-line option in advanced melanoma. Nat Rev Clin Oncol. 12(11):625–626.
31.
TerawakiSChikumaSShibayamaSHayashiTYoshidaTOkazakiTHonjoT. 2011. IFN-alpha directly promotes programmed cell death-1 transcription and limits the duration of T cell-mediated immunity. J Immunol. 186(5):2772–2779.
32.
VermaGVishnoiKTyagiAJadliMSinghTGoelASharmaAAgarwalKPrasadSCPandeyD. 2017. Characterization of key transcription factors as molecular signatures of HPV-positive and HPV-negative oral cancers. Cancer Med. 6(3):591–604.
33.
VogtPKHartJR. 2011. Pi3k and STAT3: a new alliance. Cancer Discov. 1(6):481–486.
34.
WilsonRPIvesMLRaoGLauAPayneKKobayashiMArkwrightPDPeakeJWongMAdelsteinS. 2015. Stat3 is a critical cell-intrinsic regulator of human unconventional T cell numbers and function. J Exp Med. 212(6):855–864.
35.
YangXPGhoreschiKSteward-TharpSMRodriguez-CanalesJZhuJGraingerJRHiraharaKSunHWWeiLVahediG. 2011. Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5. Nat Immunol. 12(3):247–254.
36.
YuGTBuLLHuangCFZhangWFChenWJGutkindJSKulkarniABSunZJ. 2015. PD-1 blockade attenuates immunosuppressive myeloid cells due to inhibition of CD47/SIRPalpha axis in HPV negative head and neck squamous cell carcinoma. Oncotarget. 6(39):42067–42080.
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