Prognostic role of STAT6 in patients with non-small cell lung cancer

  • O. Vynnychenko Sumy Regional Clinical Oncology Center
  • Y. Moskalenko Sumy State University
  • O. Yazykov Sumy State University
  • I. Tymchenko Kyiv Medical University
  • O. Seleznov Medical Laboratory CSD
  • O. Sulaieva Kyiv Medical University
  • R. Moskalenko Sumy State University
DOI: https://doi.org/10.15421/0224125
Keywords: lung cancer; survival; gender; immune phenotype; FOXP3; CD163; CD8

Abstract

Lung cancer is the leading cause of death from cancer in Ukraine and worldwide. The impact on the tumor microenvironment is the most promising direction for lung cancer therapy. Tumor-associated macrophages of type M2 have the most powerful immunosuppressive properties. A new potential way of influencing M2 macrophages is the signaling protein and activator of transcription 6 (STAT6). The aim of our study was to evaluate the role of STAT6 in the formation of the immunosuppressive microenvironment and the prognosis of patients with radically treated non-small cell lung cancer (NSCLC). We performed an immunohistochemical examination of the tumor tissue of 42 NSCLC patients with antibodies to CD8+, forkhead box P3 (FOXP3+), CD163+, and STAT6. The impact on survival was assessed by Cox regression analysis. The median follow-up period for the studied cohort was 57.9 ± 4.2 months. 50.0% of patients with NSCLC have high expression of STAT6. We established that STAT6 correlates with the histology of NSCLC and the gender of patients. High expression of STAT6 is significantly more determined in squamous cell carcinomas than in adenocarcinomas. In patients with squamous cell carcinomas, metastasis to regional lymph nodes is associated with an immune exclusion phenotype and is mediated by a high infiltration of tumor stroma M2 macrophages. An inflammatory immune phenotype with low CD163+, FOXP3+, and STAT6 expression is most typical for adenocarcinoma. Low STAT6 and an inflammatory immune phenotype are more common in women; high STAT6 and an immune exclusion phenotype in men. Females and patients with high CD8+ expression in tumor clusters, low CD163+ in tumor stroma, and low STAT6 expression have better overall survival. Conclusions: STAT6 overexpression is associated with immunosuppressive microenvironment and has a negative impact on recurrence-free survival and overall survival in NSCLC patients. To obtain more accurate results, it is necessary to conduct a study that includes a larger cohort of patients, in particular, female patients.

References

Allen, G. M., Frankel, N. W., Reddy, N. R., Bhargava, H. K., Yoshida, M. A., Stark, S. R., Purl, M., Lee, J., Yee, J. L., Yu, W., Li, A. W., Garcia, K. C., El-Samad, H., Roybal, K. T., Spitzer, M. H., & Lim, W. A. (2022). Synthetic cytokine circuits that drive T cells into immune-excluded tumors. Science, 378(6625), eaba1624.

Backman, M., Strell, C., Lindberg, A., Mattsson, J. S. M., Elfving, H., Brunnström, H., O'Reilly, A., Bosic, M., Gulyas, M., Isaksson, J., Botling, J., Kärre, K., Jirström, K., Lamberg, K., Pontén, F., Leandersson, K., Mezheyeuski, A., & Micke, P. (2023). Spatial immunophenotyping of the tumour microenvironment in non-small cell lung cancer. European Journal of Cancer, 185, 40–52.

Caruana, I., Simula, L., Locatelli, F., & Campello, S. (2018). T lymphocytes against solid malignancies: Winning ways to defeat tumours. Cell Stress, 2(8), 200–212.

Chai, D., Shi, S. Y., Sobhani, N., Ding, J., Zhang, Z., Jiang, N., Wang, G., Li, M., Li, H., Zheng, J., & Bai, J. (2022). IFI35 promotes renal cancer progression by inhibiting pSTAT1/pSTAT6-dependent autophagy. Cancers, 14(12), 2861.

Chen, D. S., & Mellman, I. (2013). Oncology meets immunology: the cancer-immunity cycle. Immunity, 39(1), 1–10.

Chen, Q., Qin, Z., Sun, Y., Liu, X., Pac Soo, A., Chang, E., Sun, Q., Yi, B., Wang, D. X., Zhao, H., Ma, D., & Gu, J. (2022). Dexmedetomidine activates Akt, STAT6 and IRF4 modulating cytoprotection and macrophage anti-inflammatory phenotype against acute lung injury in vivo and in vitro. Journal of Inflammation Research, 15, 2707–2720.

Cortese, N., Donadon, M., Rigamonti, A., & Marchesi, F. (2019). Macrophages at the crossroads of anticancer strategies. Frontiers in Bioscience, 24(7), 1271–1283.

Deshpand, R., Chandra, M., & Rauthan, A. (2022). Evolving trends in lung cancer: Epidemiology, diagnosis, and management. Indian Journal of Cancer, 59, S90–S105.

Faida, P., Attiogbe, M. K. I., Majeed, U., Zhao, J., Qu, L., & Fan, D. (2023). Lung cancer treatment potential and limits associated with the STAT family of transcription factors. Cellular Signalling, 109, 110797.

Faida, P., Attiogbe, M. K. I., Majeed, U., Zhao, J., Qu, L., & Fan, D. (2023). Lung cancer treatment potential and limits associated with the STAT family of transcription factors. Cellular Signalling, 109, 110797.

Fu, C., Jiang, L., Hao, S., Liu, Z., Ding, S., Zhang, W., Yang, X., & Li, S. (2019). Activation of the IL-4/STAT6 signaling pathway promotes lung cancer progression by increasing M2 myeloid cells. Frontiers in Immunology, 10, 2638.

He, K., Barsoumian, H. B., Puebla-Osorio, N., Hu, Y., Sezen, D., Wasley, M. D., Bertolet, G., Zhang, J., Leuschner, C., Yang, L., Kettlun Leyton, C. S., Fowlkes, N. W., Green, M. M., Hettrick, L., Chen, D., Masrorpour, F., Gu, M., Maazi, H., Revenko, A. S., Cortez, M. A., & Welsh, J. W. (2023). Inhibition of STAT6 with antisense oligonucleotides enhances the systemic antitumor effects of radiotherapy and anti-PD-1 in metastatic non-small cell lung cancer. Cancer Immunology Research, 11(4), 486–500.

Huang, T., Chen, B., Wang, F., Cai, W., Wang, X., Huang, B., Liu, F., Jiang, B., & Zhang, Y. (2021). Rab1A promotes IL-4R/JAK1/STAT6-dependent metastasis and determines JAK1 inhibitor sensitivity in non-small cell lung cancer. Cancer Letters, 523, 182–194.

Jensen, S. M., Meijer, S. L., Kurt, R. A., Urba, W. J., Hu, H. M., & Fox, B. A. (2003). Regression of a mammary adenocarcinoma in STAT6-/- mice is dependent on the presence of STAT6-reactive T cells. Journal of Immunology, 170(4), 2014–2021.

Kacha, A. K., Fallarino, F., Markiewicz, M. A., & Gajewski, T. F. (2000). Cutting edge: Spontaneous rejection of poorly immunogenic P1.HTR tumors by Stat6-deficient mice. Journal of Immunology, 165(11), 6024–6028.

Karpathiou, G., Papoudou-Bai, A., Ferrand, E., Dumollard, J. M., & Peoc'h, M. (2021). STAT6: A review of a signaling pathway implicated in various diseases with a special emphasis in its usefulness in pathology. Pathology, Research and Practice, 223, 153477.

Lee, H. P., Li, C. J., & Lee, C. C. (2024). EGFR overexpression and macrophage infiltration correlate with poorer prognosis in HPV-negative oropharyngeal cancer via STAT6 signaling. Head and Neck, 46(6), 1294–1303.

Lee, Y. J., Kim, B. M., Ahn, Y. H., Choi, J. H., Choi, Y. H., & Kang, J. L. (2021). STAT6 signaling mediates PPARγ activation and resolution of acute sterile inflammation in mice. Cells, 10(3), 501.

Leiter, A., Veluswamy, R. R., & Wisnivesky, J. P. (2023). The global burden of lung cancer: Current status and future trends. Nature Reviews, Clinical Oncology, 20(9), 624–639.

Li, D., Jiao, Y., Gao, W., Hu, S., Li, D., Zhao, W., Chen, P., Jin, L., Zhao, Y., Ma, Z., Wu, X., Yan, Y., Sun, W., Du, X., & Dong, G. (2022). Comprehensive analysis of the prognostic and immunotherapeutic implications of STAT family members in human colorectal cancer. Frontiers in Genetics, 13, 951252.

Liao, X., Sharma, N., Kapadia, F., Zhou, G., Lu, Y., Hong, H., Paruchuri, K., Mahabeleshwar, G. H., Dalmas, E., Venteclef, N., Flask, C. A., Kim, J., Doreian, B. W., Lu, K. Q., Kaestner, K. H., Hamik, A., Clément, K., & Jain, M. K. (2011). Krüppel-like factor 4 regulates macrophage polarization. The Journal of Clinical Investigation, 121(7), 2736–2749.

Liu, W., Zhu, F., Yan, J., Liu, Y., Chen, C., Zhang, K., Zhao, X., & Chen, J. (2020). Identification and validation of STAT6 as a prognostic and predictive biomarker in acute myeloid leukemia. OncoTargets and Therapy, 13, 11165–11176.

Lopez-Yrigoyen, M., Cassetta, L., & Pollard, J. W. (2021). Macrophage targeting in cancer. Annals of the New York Academy of Sciences, 1499(1), 18–41.

Ma, J., Chan, C. C., Huang, W. C., & Kuo, M. L. (2020). Berberine inhibits pro-inflammatory cytokine-induced IL-6 and CCL11 production via modulation of STAT6 pathway in human bronchial epithelial cells. International Journal of Medical Sciences, 17(10), 1464–1473.

Miyauchi, S., Arimoto, K. I., Liu, M., Zhang, Y., & Zhang, D. E. (2023). Reprogramming of tumor-associated macrophages via NEDD4-mediated CSF1R degradation by targeting USP18. Cell Reports, 42(12), 113560.

Mondello, P., Cuzzocrea, S., Arrigo, C., Pitini, V., Mian, M., & Bertoni, F. (2020). STAT6 activation correlates with cerebrospinal fluid IL-4 and IL-10 and poor prognosis in primary central nervous system lymphoma. Hematological Oncology, 38(1), 106–110.

Nie, X., Fu, L., Cheng, Y., Wu, X., Lv, K., Li, R., Wu, Y., Leung, G. P., Fu, C., Lee, S. M., Seto, S. W., Zhang, J., & Li, J. (2023). Garcinone E suppresses breast cancer growth and metastasis by modulating tumor-associated macrophages polarization via STAT6 signaling. Phytotherapy Research: PTR, 37(10), 4442–4456.

Pastuszak-Lewandoska, D., Domańska-Senderowska, D., Kordiak, J., Antczak, A., Czarnecka, K. H., Migdalska-Sęk, M., Nawrot, E., Kiszałkiewicz, J. M., & Brzeziańska-Lasota, E. (2017). Immunoexpression analysis of selected JAK/ STAT pathway molecules in patients with non-small-cell lung cancer. Polish Archives of Internal Medicine, 127(11), 758–764.

Rahal, O. M., Wolfe, A. R., Mandal, P. K., Larson, R., Tin, S., Jimenez, C., Zhang, D., Horton, J., Reuben, J. M., McMurray, J. S., & Woodward, W. A. (2018). Blocking interleukin (IL)4- and IL13-mediated phosphorylation of STAT6 (Tyr641) decreases M2 polarization of macrophages and protects against macrophage-mediated radioresistance of inflammatory breast cancer. International Journal of Radiation Oncology, Biology, Physics, 100(4), 1034–1043.

Ray, J. L., Shaw, P. K., Postma, B., Beamer, C. A., & Holian, A. (2022). Nanoparticle-induced airway eosinophilia is independent of ILC2 signaling but associated with sex differences in macrophage phenotype development. Journal of Immunology, 208(1), 110–120.

Salguero-Aranda, C., Sancho-Mensat, D., Canals-Lorente, B., Sultan, S., Reginald, A., & Chapman, L. (2019). STAT6 knockdown using multiple siRNA sequences inhibits proliferation and induces apoptosis of human colorectal and breast cancer cell lines. PloS One, 14(5), e0207558.

Shu, H., Ren, Z. J., Li, H., Zhang, Y., Yin, C., & Nie, F. (2024). Ultrasound-mediated nanobubbles loaded with STAT6 siRNA inhibit TGF-β1-EMT axis in LUSC cells via overcoming the polarization of M2-TAMs. European Journal of Pharmaceutical Sciences: Official Journal of the European Federation for Pharmaceutical Sciences, 202, 106894.

Stütz, A. M., Pickart, L. A., Trifilieff, A., Baumruker, T., Prieschl-Strassmayr, E., & Woisetschläger, M. (2003). The Th2 cell cytokines IL-4 and IL-13 regulate found in inflammatory zone 1/resistin-like molecule alpha gene expression by a STAT6 and CCAAT/enhancer-binding protein-dependent mechanism. Journal of Immunology, 170(4), 1789–1796.

Sulaieva, O., Chernenko, O., Selesnov, O., Nechay, O., Maievskyi, O., Falalyeyeva, T., Kobyliak, N., Tsyryuk, O., Penchuk, Y., & Shapochka, D. (2020). Mechanisms of the impact of Hashimoto thyroiditis on papillary thyroid carcinoma progression: relationship with the tumor immune microenvironment. Endocrinology and Metabolism, 35(2), 443–455.

Valladao, A. C., Frevert, C. W., Koch, L. K., Campbell, D. J., & Ziegler, S. F. (2016). STAT6 regulates the development of eosinophilic versus neutrophilic asthma in response to alternaria alternata. Journal of Immunology, 197(12), 4541–4551.

Xu, L., Xie, X., & Luo, Y. (2021). The role of macrophage in regulating tumour microenvironment and the strategies for reprogramming tumour-associated macrophages in antitumour therapy. European Journal of Cell Biology, 100(2), 151153.

Yang, L. Q., Wang, L., Zuo, L. K., Ma, Z. P., Yan, S. F., Yang, M. H., Liu, B., & Li, X. X. (2022). Expression and prognostic analysis of STAT6(YE361) in Hodgkin lymphoma. Pathology, Research and Practice, 231, 153781.

Yu, D., Zhao, Z., Wang, L., Qiao, S., Yang, Z., Wen, Q., & Zhu, G. (2022). SOX21-AS1 activated by STAT6 promotes pancreatic cancer progression via up-regulation of SOX21. Journal of Translational Medicine, 20(1), 511.

Yu, J. E., Yeo, I. J., Son, D. J., Yun, J., Han, S. B., & Hong, J. T. (2022). Anti-Chi3L1 antibody suppresses lung tumor growth and metastasis through inhibition of M2 polarization. Molecular Oncology, 16(11), 2214–2234.

Zhao, H., Moarbes, V., Gaudreault, V., Shan, J., Aldossary, H., Cyr, L., & Fixman, E. D. (2019). Sex differences in IL-33-induced STAT6-dependent type 2 airway inflammation. Frontiers in Immunology, 10, 859.

Zhou, C., Lu, C., Pu, H., Li, D., & Zhang, L. (2020). TRAF6 promotes IL-4-induced M2 macrophage activation by stabilizing STAT6. Molecular Immunology, 127, 223–229.

Published
2024-10-26
How to Cite
Vynnychenko, O., Moskalenko, Y., Yazykov, O., Tymchenko, I., Seleznov, O., Sulaieva, O., & Moskalenko, R. (2024). Prognostic role of STAT6 in patients with non-small cell lung cancer . Regulatory Mechanisms in Biosystems, 15(4), 868-874. https://doi.org/10.15421/0224125
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Vol 15 No 4 (2024): Regulatory Mechanisms in Biosystems
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