RESUMEN
To date, immune check-point inhibitors (ICIs), particularly inhibitors of programmed cell death-1 (PD-1) and PD ligand-1 (PD-L1) have become prominent in cancer treatment and also improved life expectancy of cancer patients. As key regulators of PD-1/PD-L1 axis, the recruitment of tumor-associated macrophages (TAMs) enhances aggressive and invasive properties of tumors in immunosuppressive tumor microenvironment (TME) and promotes epithelial-mesenchymal transition (EMT). The aims of the study were first to characterize the critical links among PD-L1, TME and EMT process and, further, to explore the sensitivity of different chemical agents to different PD-L1 expression groups. Bioinformatical analysis revealed that PD-L1 was highly expressed in OSCC and higher PD-L1 expression correlated with worse survival in patients. Notably, PD-L1 was positively correlated with macrophages infiltration and EMT markers gene expression. Moreover, patients in the PD-L1high group were at a significant chance of benefiting from ICI treatment and they also showed higher sensitivity to the chemical drugs (olaparib, paclitaxel, docetaxel, and pazopanib). These findings implicate PD-L1 could serve as a novel target for prognostic and therapeutic approaches in OSCC patients; PD-L1-mediated immune evasion might be attributable to the infiltration of macrophages, resulting EMT progress; Chemical agents in combination with PD-L1 inhibitor could be served as personalized treatment plan for OSCC patients so as to maximize patient benefit.
Asunto(s)
Antígeno B7-H1/metabolismo , Transición Epitelial-Mesenquimal , Neoplasias de la Boca/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Microambiente Tumoral , Macrófagos Asociados a Tumores/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/genética , Línea Celular Tumoral , Quimiocinas/metabolismo , Bases de Datos Genéticas , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/genética , Neoplasias de la Boca/inmunología , Transducción de Señal , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Resultado del Tratamiento , Microambiente Tumoral/inmunología , Macrófagos Asociados a Tumores/inmunologíaRESUMEN
BACKGROUND: Although estrogen deficiency has been proposed as a risk factor for oral mucosal inflammatory diseases in post-menopausal women, the mechanisms involved remain unclear. This study aimed to investigate the effect of 17ß-estradiol (E2) on the inflammatory response stimulated by interleukin-1 beta (IL-1ß) in human oral mucosal epithelial cells (hOMECs) and its possible mechanism. METHODS: Primary hOMECs were obtained from female infants and cultured in keratinocyte growth medium. The hOMECs at second passage were collected and stimulated by 10-7 mol/L ICI182,780 or 10-7 mol/L G1 for 1 hour, E2 (10-7 mol/L, 10-8 mol/L, 10-9 mol/L) for 36 hour, 100 ng/mL IL-1ß for 12 hours, respectively. Human beta-2 defensin (hBD-2), tumor necrosis factor-alpha (TNF)-α, IL-6, IL-8, estrogen receptor-alpha (ERα), estrogen receptor-beta (ERß), and G protein-coupled receptor 30 (GPR30) mRNA levels and protein levels were measured by real-time quantitative polymerase chain reaction (RT-qPCR), enzyme-linked immunosorbent assay (ELISA), and Western Blot (WB), respectively. RESULTS: Expression of hBD-2 and inflammatory cytokines increased after IL-1ß stimulation, which was down-regulated by E2 pre-treatment. With ICI182,780, the suppression of E2 on hBD-2 mRNA was attenuated. With G1, the mRNA expression and protein expression of hBD-2 were reduced. CONCLUSION: Pre-treatment of hOMECs with E2 at physiological concentrations inhibited the IL-1ß-induced expression of hBD-2 and inflammatory cytokines. The protective effects of E2 suggest its potential use treating oral inflammatory diseases in clinical practice.