Investigation of salivary interleukin-17 in patients with oral squamous cell carcinoma

Abstract

Background: Oral squamous cell carcinoma (OSCC) is a common aggressive cancer with few noninvasive biomarkers for early detection. A-17͏, a pro-inflammatory cytokine involved in tumor progression could be used as a salivary biomarker for the diagnosis and monitoring of OSCC. Objectives: To measure and compare levels of IL-17 in saliva of OSCC patients and healthy controls as well as to evaluate the expression of IL-17 in relation to tumor location and patient gender. Methods: In the Medical City Complex, Baghdad, Iraq a case-control study was carried out between March 2024 and January 2025. In total, 90 participants were enrolled; patients and controls matched for age and gender with 55 OSCC patients and 35 healthy controls. Clinically and histopathologically confirmed OSCC. Unstimulated saliva samples were collected under standardized conditions and analyzed for IL-17 concentration by using a commercially available ELISA kit. Statistical analyses were also carried out to compare IL-17 levels between groups as well as associations with tumor location and gender. Results: The OSCC patients had significantly higher salivary IL-17 levels (86.22 ± 19.56 pg/mL) as compared to healthy controls (44.12 ± 13.24 pg/mL) (T = 5.87, p = 0.022). Tumor location showed a significant association with the values of IL-17 (F = 9.12, p = 0.004). The highest values were for tumors in buccal mucosa, gingiva, and tongue; the lowest was for tumors in the palate. No significant difference was noted between males and females regarding IL-17 levels (p=0.11). Conclusion: High levels of salivary IL-17 are linked to OSCC and its level changes with the site of the tumor lesion, which suggests IL-17 as a good easy test for finding and watching OSCC. Being male or female does not seem to affect IL-17 levels.

Keywords:

Interleukin-17, oral lesions, OSCC, gingiva, palate

References

Al-Fahham, A.A. (2018) Development of New LSD Formula when Unequal Observations Numbers of Observations Are. Open Journal of Statistics, , 8, 258-263.https://doi.org/10.4236/ojs.2018.82016.

Blauvelt, A., & Chiricozzi, A. (2018). The immunologic role of IL-17 in inflammatory and neoplastic skin diseases. Journal of Investigative Dermatology, 138(1), 54–60. https://doi.org/10.1016/j.jid.2017.06.024

Chang, S.., Mirabolfathinejad, Seyedeh Golsar., Katta, Harshadadevi., Cumpian, Amber M.., Gong, L.., Caetano, M.., Moghaddam, S.., & Dong, C.. (2014). T helper 17 cells play a critical pathogenic role in lung cancer. Proceedings of the National Academy of Sciences , 111 , 5664 - 5669 . http://doi.org/10.1073/pnas.1319051111

Costa, Nádia do Lago., Valadares, M.., Souza, P.., Mendonça, E.., Oliveira, J. C.., Silva, T. A.., & Batista, A.. (2013). Tumor-associated macrophages and the profile of inflammatory cytokines in oral squamous cell carcinoma.. Oral oncology , 49 3 , 216-23 . http://doi.org/10.1016/j.oraloncology.2012.09.012

Gelderblom, M., Gallizioli, M., Ludewig, P., Thom, V., Arunachalam, P., Rissiek, B., ... & Magnus, T. (2012). IL-17 shapes the post-stroke immune response. Journal of Cerebral Blood Flow & Metabolism, 32(8), 1559–1567. https://doi.org/10.1038/jcbfm.2012.56

Greene, Sarah., Robbins, Y.., Mydlarz, W.., Huynh, Angel., Schmitt, N.., Friedman, J.., Horn, Lucas A., Palena, C.., Schlom, J.., Maeda, D.., Zebala, J.., Clavijo, Paul E., & Allen, C.. (2019). Inhibition of MDSC Trafficking with SX-682, a CXCR1/2 Inhibitor, Enhances NK-Cell Immunotherapy in Head and Neck Cancer Models. Clinical Cancer Research , 26 , 1420 - 1431 . http://doi.org/10.1158/1078-0432.CCR-19-2625

Harlan, L.., Lynch, C.., Keegan, T.., Hamilton, A.., Wu, Xiao-Cheng., Kato, I.., West, M.., Cress, R.., Schwartz, S.., Smith, Ashley Wilder., Deapen, D.., Stringer, S.., & Potosky, A.. (2011). Recruitment and follow-up of adolescent and young adult cancer survivors: the AYA HOPE Study. Journal of Cancer Survivorship , 5 , 305 - 314 . http://doi.org/10.1007/s11764-011-0173-y

Jin, W., & Dong, C. (2013). IL-17 cytokines in immunity and inflammation. Emerging Microbes & Infections, 2(1), e60. https://doi.org/10.1038/emi.2013.58

Johnson, Daniel E.., Burtness, B.., Leemans, C. R.., Lui, V.., Bauman, J.., & Grandis, J.. (2020). Head and neck squamous cell carcinoma. Nature Reviews Disease Primers , 6 , 1-22 . http://doi.org/10.1038/s41572-020-00224-3

Karakasheva, T. A., Lin, E. W., Tang, Q., Qiao, E., Waldron, T. J., Soni, M., ... & Rustgi, A. K. (2018). IL-17 signaling in the tumor microenvironment promotes tumor progression and immune evasion. Frontiers in Immunology, 9, 376. https://doi.org/10.3389/fimmu.2018.00376

Kuwabara, T., Ishikawa, F., Kondo, M., & Kakiuchi, T. (2017). The role of IL-17 and related cytokines in inflammatory autoimmune diseases. Mediators of Inflammation, 2017, 3908061. https://doi.org/10.1155/2017/3908061

Machiels, J.., Machiels, J.., Leemans, C.., Golusiński, W.., Grau, C.., Licitra, L.., & Grégoire, V.. (2020). Squamous cell carcinoma of the oral cavity, larynx, oropharynx and hypopharynx: EHNS-ESMO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up.. Annals of oncology : official journal of the European Society for Medical Oncology , 31 11 , 1462-1475

Markopoulos, A.. (2012). Current Aspects on Oral Squamous Cell Carcinoma. The Open Dentistry Journal , 6 , 126 - 130 . http://doi.org/10.2174/1874210601206010126

McGeachy, M. J., Cua, D. J., & Gaffen, S. L. (2019). The IL-17 family of cytokines in health and disease. Immunity, 50(4), 892–906. https://doi.org/10.1016/j.immuni.2019.03.021

Mills, K. H. G. (2022). Regulation of immune responses by IL-17 and IL-17-producing cells. European Journal of Immunology, 52(1), 15–30. https://doi.org/10.1002/eji.202149518

Moschen, A. R., Tilg, H., & Raine, T. (2018). IL-12, IL-23 and IL-17 in inflammatory bowel disease. Nature Reviews Gastroenterology & Hepatology, 16, 1–17. https://doi.org/10.1038/s41575-018-0084-y

Sahibzada, Haafsa Arshad., Khurshid, Z.., Khan, Rabia Sannam., Naseem, M.., Siddique, Khalid Mahmood., Mali, M.., & Zafar, Muhammad Sohail. (2017). Salivary IL-8, IL-6 and TNF-α as Potential Diagnostic Biomarkers for Oral Cancer. Diagnostics , 7 . http://doi.org/10.3390/diagnostics7020021

Sasahira, T.., & Kirita, T.. (2018). Hallmarks of Cancer-Related Newly Prognostic Factors of Oral Squamous Cell Carcinoma. International Journal of Molecular Sciences , 19 . http://doi.org/10.3390/ijms19082413

Shaban, M.., Khurram, S.., Fraz, M.., Alsubaie, Najah., Masood, Iqra., Mushtaq, S.., Hassan, Maria., Loya, A.., & Rajpoot, N.. (2019). A Novel Digital Score for Abundance of Tumour Infiltrating Lymphocytes Predicts Disease Free Survival in Oral Squamous Cell Carcinoma. Scientific Reports , 9 . http://doi.org/10.1038/s41598-019-49710-z

Sridharan, G.., Ramani, P.., Patankar, Sangeeta R.., & Vijayaraghavan, R.. (2019). Evaluation of salivary metabolomics in oral leukoplakia and oral squamous cell carcinoma. Journal of Oral Pathology & Medicine , 48 , 299–306

Tang, Haikuo., Wu, Zhiyuan., Zhang, Jianping., & Su, B.. (2013). Salivary lncRNA as a potential marker for oral squamous cell carcinoma diagnosis.. Molecular medicine reports , 7 3 , 761-6 . http://doi.org/10.3892/mmr.2012.1254

Wakita, D.., Sumida, Kentaro., Iwakura, Y.., Nishikawa, H.., Ohkuri, T.., Chamoto, K.., Kitamura, H.., & Nishimura, T.. (2010). Tumor‐infiltrating IL‐17‐producing γδ T cells support the progression of tumor by promoting angiogenesis. European Journal of Immunology , 40 . http://doi.org/10.1002/eji.200940157

Wang, K., Kim, M. K., Di Caro, G., Wong, J., Shalapour, S., Wan, J., ... & Karin, M. (2017). Interleukin-17 induces expression of programmed cell death ligand 1 in colorectal cancer cells. Immunity, 46(6), 1056–1068.e4. https://doi.org/10.1016/j.immuni.2017.06.010

Wu, Lei., Deng, W.., Huang, Cong-Fa., Bu, L.., Yu, G.., Mao, L.., Zhang, Wen-Feng., Liu, Bing., & Sun, Zhi‐Jun. (2017). Expression of VISTA correlated with immunosuppression and synergized with CD8 to predict survival in human oral squamous cell carcinoma. Cancer Immunology, Immunotherapy , 66 , 627-636 . http://doi.org/10.1007/s00262-017-1968-0

Yuan, Zhuang., Peng, Liu-sheng., Zhao, Yongliang., Shi, Yun., Mao, X.., Chen, Weisan., Pang, K.., Liu, Xiao-fei., Liu, Tao., Zhang, Jin-yu., Zeng, H.., Liu, Kai-yun., Guo, G.., Tong, Wen-de., Shi, Yan., Tang, B.., Li, Na., Yu, Shu., Luo, P.., Zhang, Wei-jun., Lu, D.., Yu, P.., & Zou, Q.. (2012). CD8(+) T cells that produce interleukin-17 regulate myeloid-derived suppressor cells and are associated with survival time of patients with gastric cancer.. Gastroenterology , 143 4 , 951-62.e8 . http://doi.org/10.1053/j.gastro.2012.06.010

Zhao, Junjie., Chen, Xing., Herjan, T.., & Li, Xiaoxia. (2019). The role of interleukin-17 in tumor development and progression. The Journal of Experimental Medicine, 217. http://doi.org/10.1084/jem.20190297