Mechanism of Porphyromonas gingivalis Inducing the Formation of a Local Immunosuppressive Microenvironment in Oral Squamous Cell Carcinoma
Abstract
To investigate the role of Porphyromonas gingivalis (P.g) in the tumor microenvironment of oral squamous cell carcinoma (OSCC) and provide new insights for OSCC treatment.
Methods
The murine squamous cell carcinoma cell line SCC7 was cultured in vitro, and a tumor-bearing model was established with C57BL/6 mice. Experimental mice were randomly assigned to the P.g activation group and the control group (n = 5 per group) based on the principles of randomization and control. After 16 days of feeding, the mice were sacrificed, and the weight and volume of the tumors in the two groups of mice were recorded. Immunohistochemistry was performed to analyze the expression levels of CD4+ T cells, CD8+ T cells, transforming growth factor-β (TGF-β), interleukin-10 (IL-10), interferon-γ (IFN-γ), E-cadherin, N-cadherin, Twist, vascular endothelial growth factor (VEGF), CD31, and Ki67 in the tumor tissues. Flow cytometry was performed to examine the tumor samples from the two groups of mice, and to quantify the proportional differences of CD4+ T cells, CD8+ T cells, as well as CD69+ and CD103+ on T lymphocytes from the samples.
Results
The immunohistochemistry results showed that the expression of CD4+ T cells and their function-related cytokines in the tumor tissues of the activation group was higher than that of the control group, and the differences were statistically significant (P < 0.05). According to the flow cytometry results, the proportion of CD8+ T cells in the tumor tissues of the activation group decreased, and the proportion of CD103+CD8+ T cells, which played an anti-tumor immune role, also decreased, with the differences being statistically significant compared with the control group (P < 0.05). In addition, the expression of all the cytokines associated with malignant tumor phenotypes in the activation group increased, and the differences were statistically significant compared with the control group (P < 0.05).
Conclusion
This study verified through animal experiments that by enhancing the infiltration of CD4+ T cells and suppressing the immunosuppressive function of CD8+ T cells in the OSCC tumor microenvironment, P.g enables tumor cell immune escape and accelerates epithelial-mesenchymal transition, angiogenesis, and tumor cell proliferation.
Keywords: Oral squamous cell carcinoma, Porphyromonas gingivalis, Immunosuppressive microenvironment, Malignant biological behavior of tumors
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XUE Y, SONG X, FAN S, et al. The role of tumor-associated macrophages in oral squamous cell carcinoma. Front Physiol, 2022, 13: 959747. doi: 10. 3389/fphys.2022.959747.
MODY M D, ROCCO J W, YOM S S, et al. Head and neck cancer. Lancet, 2021, 398(10318): 2289-2299. doi: 10.1016/S0140-6736(21)01550-6.
LI R, WANG Y, DU J, et al. Graphene oxide loaded with tumor-targeted peptide and anti-cancer drugs for cancer target therapy. Sci Rep, 2021, 11(1): 1725. doi: 10.1038/s41598-021-81218-3.
BILOTTA M T, ANTIGNANI A, FITZGERALD D J. Managing the TME to improve the efficacy of cancer therapy. Front Immunol, 2022, 13: 954992. doi: 10.3389/fimmu.2022.954992.
KIM S, MIN H, NAH J, et al. Defective N-glycosylation in tumor-infiltrating CD8(+) T cells impairs IFN-gamma-mediated effector function. Immunol Cell Biol, 2023, 101(7): 610-624. doi: 10.1111/imcb.12647.
YANG G, CAI S, HU M, et al. Functional status and spatial architecture of tumor-infiltrating CD8+ T cells are associated with lymph node metastases in non-small cell lung cancer. J Transl Med, 2023, 21(1): 320. doi: 10.1186/s12967-023-04154-y.
CENERENTI M, SAILLARD M, ROMERO P, et al. The era of cytotoxic CD4 T cells. Front Immunol, 2022, 13: 867189. doi: 10.3389/fimmu.2022. 867189.
MANFIOLETTI G, FEDELE M. Epithelial-mesenchymal transition (EMT). Int J Mol Sci, 2023, 24(14): 11386. doi: 10.3390/ijms241411386.
AKRIDA I, MULITA F, PLACHOURI K M, et al. Epithelial to mesenchymal transition (EMT) in metaplastic breast cancer and phyllodes breast tumors. Med Oncol, 2023, 41(1): 20. doi: 10.1007/s12032-023-02259-4.
CHEN Y P, WANG Y Q, LV J W, et al. Identification and validation of novel microenvironment-based immune molecular subgroups of head and neck squamous cell carcinoma: implications for immunotherapy. Ann Oncol, 2019, 30(1): 68-75. doi: 10.1093/annonc/mdy470.
JIANG Y, ZHAN H. Communication between EMT and PD-L1 signaling: New insights into tumor immune evasion. Cancer Lett, 2020, 468: 72-81. doi: 10.1016/j.canlet.2019.10.013.
LI B, CUI Y, NAMBIAR D K, et al. The immune subtypes and landscape of squamous cell carcinoma. Clin Cancer Res, 2019, 25(12): 3528-3537. doi: 10.1158/1078-0432.CCR-18-4085.
SINGH S, SINGH A K. Porphyromonas gingivalis in oral squamous celcarcinoma: a review. Microbes Infect, 2022, 24(3): 104925. doi: 10. 1016/imicinf.2021.104925.
PENG X, CHENG L, YOU Y, et al. Oral microbiota in human systematic diseases. Int J Oral Sci, 2022, 14(1): 14. doi: 10.1038/s41368-022-00163-7.
WEN L, MU W, LU H, et al. Porphyromonas gingivalis promotes oral squamous cell carcinoma progression in an immune microenvironment. J Dent Res, 2020, 99(6): 666-675. doi: 10.1177/0022034520909312.
LIU X, XU L M, LIU L Q, et al. Effect of porphyromonas gingivalis (P. g) upregulation of CCL20 expression on oral squamous cell phenotyp. J Xinjiang Med Univ, 2024, 47(3): 322-328. doi: 10.3969/j.issn.1009-5551. 2024.03.004.
KIKUCHI M, YAMASHITA D, HARA S, et al. Clinical significance of tumor-associated immune cells in patients with oral squamous cell carcinoma. Head Neck, 2021, 43(2): 534-543. doi: 10.1002/hed.26498.
YU W, LEI Q, YANG L, et al. Contradictory roles of lipid metabolism in immune response within the tumor microenvironment. J Hematol Oncol, 2021, 14(1): 187. doi: 10.1186/s13045-021-01200-4.
HU J, LAZAR A J, INGRAM D, et al. Cell membrane-anchored and tumor-targeted IL-12 T-cell therapy destroys cancer-associated fibroblasts and disrupts extracellular matrix in heterogenous osteosarcoma xenograft models. J Immunother Cancer, 2024, 12(1): e006991. doi: 10.1136/jitc-2023-006991.
IRFAN M, DELGADO R, FRIAS-LOPEZ J. The oral microbiome and cancer. Front Immunol, 2020, 11: 591088. doi: 10.3389/fimmu.2020. 591088.
CHEN Y, CHEN X, YU H, et al. Oral microbiota as promising diagnostic biomarkers for gastrointestinal cancer: a systematic review. Onco Targets Ther, 2019, 12: 11131-11144. doi: 10.2147/OTT.S230262.
SUN J, TANG Q, YU S, et al. Role of the oral microbiota in cancer evolution and progression. Cancer Med, 2020, 9(17): 6306-6321. doi: 10. 1002/cam4.3206.
PERERA M, Al-HEBSHI N N, SPEICHER D J, et al. Emerging role of bacteria in oral carcinogenesis: a review with special reference to perio-pathogenic bacteria. J Oral Microbiol, 2016, 8: 32762. doi: 10.3402/jom.v8.32762.
GAO R, ZHANG W, JIANG Y, et al. Eldecalcitol effectively prevents alveolar bone loss by partially improving Th17/Treg cell balance in diabetes-associated periodontitis. Front Bioeng Biotechnol, 2023, 11: 1070117. doi: 10.3389/fbioe.2023.1070117.
SHIMIZU S, HIRATSUKA H, KOIKE K, et al. Tumor-infiltrating CD8(+) T-cell density is an independent prognostic marker for oral squamous cell carcinoma. Cancer Med, 2019, 8(1): 80-93. doi: 10.1002/ cam4.1889.
IIJIMA N, IWASAKI A. Tissue instruction for migration and retention of TRM cells. Trends Immunol, 2015, 36(9): 556-564. doi: 10.1016/j.it.2015.07.002.
MATSUOKA T, YASHIRO M. The role of the transforming growth factor-β signaling pathway in gastrointestinal cancers. Biomolecules, 2023, 13(10): 1551. doi: 10.3390/biom13101551.
WANG F, YI J, CHEN Y, et al. PRSS2 regulates EMT and metastasis via MMP-9 in gastric cancer. Acta Histochem, 2023, 125(6): 152071. doi: 10. 1016/j.acthis.2023.152071.
HU X, XIANG F, FENG Y, et al. Neutrophils promote tumor progression in oral squamous cell carcinoma by regulating EMT and JAK2/STAT3 signaling through chemerin. Front Oncol, 2022, 12: 812044. doi: 10.3389/fonc.2022.812044.
SWAIN S, NISHAT R, RAMACHANDRAN S, et al. Comparative evaluation of immunohistochemical expression of MCM2 and Ki67 in oral epithelial dysplasia and oral squamous cell carcinoma. J Cancer Res Ther, 2022, 18(4): 997-1002. doi: 10.4103/jcrt.JCRT_10_20.
LOPEZ-GRANIEL C M, TAMEZ D L D, MENESES-GARCIA A, et al. Tumor angiogenesis as a prognostic factor in oral cavity carcinomas. J Exp Clin Cancer Res, 2001, 20(4): 463-468.
SMITH B D, SMITH G L, CARTER D, et al. Prognostic significance of vascular endothelial growth factor protein levels in oral and oropharyngeal squamous cell carcinoma. J Clin Oncol, 2000, 18(10): 2046-2052. doi: 10.1200/JCO.2000.18.10.2046.
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