Objective: Despite the existence of several
therapeutic strategies, the management of cervical cancer remains challenging.
Our region hasvery little data on the interaction between the immune system and the
clinical response to chemotherapy. This work examines plasma levels of
galectin-3 (Gal-3) and percentages of activated T cells in patients with
cervical cancer treated with chemotherapy and investigates if there is a
relationship between the rates of these two elements. Methods: We
compared data from 37 patients with cervical cancer undergoing chemotherapy and
42 controls with normal cervical cytology. Plasma Gal-3 concentrations were
assessed by ELISA and expression of activation markers by T cells (CD69 and
HLA-DR) was assessed by flow cytometry at three different time points during chemotherapy. Results: Our results showed that patients had a significantly higher concentration of Gal-3 compared to
controls (4.025 vs. 1.340, p < 0.001), similarly, they had a significantly high percentage of activated
lymphocytes (2.610 vs. 0.731; p < 0.0001). According to the response to treatment, patients
with no response to treatment had a lower concentration of circulating Gal-3but had approximately the same percentage of activated CD4 and CD8
lymphocytes as patients with a partial or total response. In addition, we found
a positive correlation between the Gal-3 level and CD4 T cells expressing the
activation
References
[1]
Arbyn, M., Weiderpass, E., Bruni, L., de Sanjose, S. and Saraiya, M. (2020) Estimates of Incidence and Mortality of Cervical Cancer in 2018: A Worldwide Analysis. The Lancet Global Health, 8, e191-e203. https://doi.org/10.1016/S2214-109X(19)30482-6
[2]
Parkin, D.M., Hammerl, L., Ferlay, J. and Kantelhardt, E.J. (2020) Cancer in Africa 2018: The Role of Infections. International Journal of Cancer, 146, 2089-2103. https://doi.org/10.1002/ijc.32538
[3]
Barondes, S.H., Castronovo, V., Cooper, D.N., Cummings, R.D., Drickamer, K., et al. (1994) Galectins: A Family of Animal β-Galactoside-Binding Lectins. Cell, 76, 597-598. https://doi.org/10.1016/0092-8674(94)90498-7
[4]
Funasaka, T., Raz, A. and Nangia-Makker, P. (2014) Nuclear Transport of Galectin-3 and Its Therapeutic Implications. Seminars in Cancer Biology, 27, 30-38. https://doi.org/10.1016/j.semcancer.2014.03.004
[5]
Dumic, J., Dabelic, S. and Flögel, M. (2006) Galectin-3: An Open-Ended Story. Biochim et Biophys Acta, 1760, 616-635. https://doi.org/10.1016/j.bbagen.2005.12.020
[6]
Gao, X., Balan, V., Tai, G. and Raz, A. (2014) Galectin-3 Induces Cell Migration Via a Calcium-Sensitive MAPK/ERK1/2 Pathway. Oncotarget, 5, 2077-2084. https://doi.org/10.18632/oncotarget.1786
[7]
Inohara, H., Akahani, S., Koths, K. and Raz, A. (1996) Interactions between Galectin-3 and Mac-2-Binding Protein Mediate Cell-Cell Adhesion. Cancer Research, 56, 4530-4534.
[8]
Markowska, A.I., Jefferies, K.C. and Panjwani, N. (2011) Galectin-3 Protein Modulates Cell Surface Expression and Activation of Vascular Endothelial Growth Factor Receptor 2 in Human Endothelial Cells. Journal of Biological Chemistry, 286, 29913-29921. https://doi.org/10.1074/jbc.M111.226423
[9]
Chen, H.Y., Fermin, A., Vardhana, S., Weng, I.C., Lo, K.F., et al. (2009) Galectin-3 Negatively Regulates TCR-Mediated CD4+ T-Cell Activation at the Immunological Synapse. Proceedings of the National Academy of Sciences of the United States of America, 106, 14496-14501. https://doi.org/10.1073/pnas.0903497106
[10]
Nangia-Makker, P., Nakahara, S., Hogan, V. and Raz, A. (2007) Galectin-3 in Apoptosis, a Novel Therapeutic Target. Journal of Bioenergetics and Biomembranes, 39, 79-84. https://doi.org/10.1007/s10863-006-9063-9
[11]
Sakaki, M., Oka, N., Nakanishi, R., Yamaguchi, K., Fukumori, T., et al. (2008) Serum Level of Galectin-3 in Human Bladder Cancer. The Journal of Medical Investigation, 55, 127-132. https://doi.org/10.2152/jmi.55.127
[12]
Schoeppner, H.L., Raz, A., Ho, S.B., Bresalier, R.S. (1995) Expression of an Endogenous Galactose-Binding Lectin Correlates with Neoplastic Progression in the Colon. Cancer, 75, 2818-2826. https://doi.org/10.1002/1097-0142(19950615)75:12<2818::AID-CNCR2820751206>3.0.CO;2-#
[13]
Berberat, P.O., Friess, H., Wang, L., Zhu, Z., Bley, T., et al. (2001) Comparative Analysis of Galectins in Primary Tumors and Tumor Metastasis in Human Pancreatic Cancer. Journal of Histochemistry & Cytochemistry, 49, 539-549. https://doi.org/10.1177/002215540104900414
[14]
Orlandi, F., Saggiorato, E., Pivano, G., Puligheddu, B., Termine, A., et al. (1998) Galectin-3 Is a Presurgical Marker of Human Thyroid Carcinoma. Cancer Research, 58, 3015-3020.
[15]
Yamaki, S., Fujii, T., Yajima, R., Hirakata, T., Yamaguchi, S., et al. (2013) Clinicopathological Significance of Decreased Galectin-3 Expression and the Long-Term Prognosis in Patients with Breast Cancer. Surgery Today, 43, 901-905. https://doi.org/10.1007/s00595-012-0378-3
[16]
Gilson, R.C., Gunasinghe, S.D., Johannes, L. and Gaus, K. (2019) Galectin-3 Modulation of T-Cell Activation: Mechanisms of Membrane Remodelling. Progress in Lipid Research, 76, Article 101010. https://doi.org/10.1016/j.plipres.2019.101010
[17]
Demetriou, M., Granovsky, M., Quaggin, S. and Dennis, J.W. (2001) Negative Regulation of T-Cell Activation and Autoimmunity by Mgat5 N-Glycosylation. Nature, 409, 733-739. https://doi.org/10.1038/35055582
[18]
Schindler, E.I., Szymanski, J.J., Hock, K.G., Geltman, E.M. and Scott, M.G. (2016) Short-and Long-Term Biologic Variability of Galectin-3 and Other Cardiac Biomarkers in Patients with Stable Heart Failure and Healthy Adults. Clinical Chemistry, 62, 360-366. https://doi.org/10.1373/clinchem.2015.246553
[19]
Balan, V., Wang, Y., Nangia-Makker, P., Kho, D., Bajaj, M., et al. (2013) Galectin-3: A Possible Complementary Marker to the PSA Blood Test. Oncotarget, 4, 542-549. https://doi.org/10.18632/oncotarget.923
[20]
Saussez, S., Lorfevre, F., Lequeux, T., Laurent, G., Chantrain, G., et al. (2008) The Determination of the Levels of Circulating Galectin-1 and-3 in HNSCC Patients Could be Used to Monitor Tumor Progression and/or Responses to Therapy. Oral Oncol, 44, 86-93. https://doi.org/10.1016/j.oraloncology.2006.12.014
[21]
Iurisci, I., Tinari, N., Natoli, C., Angelucci, D., Cianchetti, E., et al. (2000) Concentrations of Galectin-3 in the Sera of Normal Controls and Cancer Patients. Clincal Cancer Research, 6, 1389-1393.
[22]
Shimura, T., Shibata, M., Gonda, K., Nakajima, T., Chida, S., et al. (2016) Circulating Galectin-3 Correlates with Angiogenetic Factors and Indicators of Systemic Inflammation in Patients with Stage IV Esophageal Cancer. Annals of Cancer Research Therapy, 24, 30-34. https://doi.org/10.4993/acrt.24.30
[23]
Xie, L., Ni, W.K., Chen, X.D., Xiao, M.B., Chen, B.Y., et al. (2012) The Expressions and Clinical Significances of Tissue and Serum Galectin-3 in Pancreatic Carcinoma. Journal of Cancer Research and Clinical Oncology, 138, 1035-1043. https://doi.org/10.1007/s00432-012-1178-2
[24]
Isic, T., Savin, S., Cvejic, D., Marecko, I., Tatic, S., et al. (2010) Serum Cyfra 21.1 and Galectin-3 Protein Levels in Relation to Immunohistochemical Cytokeratin 19 and Galectin-3 Expression in Patients with Thyroid Tumors. Journal of Cancer Research and Clinical Oncology, 136, 1805-1812. https://doi.org/10.1007/s00432-010-0838-3
[25]
Cheng, D., Liang, B. and Li, Y. (2015) Serum Galectin-3 as a Potential Marker for Gastric Cancer. Medical Science Monitor, 21, 755-760. https://doi.org/10.12659/MSM.892386
[26]
Balasubramanian, K., Vasudevamurthy, R., Venkateshaiah, S.U., Thomas, A., Vishweshwara, A., et al. (2009) Galectin-3 in Urine of Cancer Patients: Stage and Tissue Specificity. Journal of Cancer Research and Clinical Oncology, 135, 355-363. https://doi.org/10.1007/s00432-008-0481-4
[27]
Liu, J., Cheng, Y., He, M. and Yao, S. (2014) Vascular Endothelial Growth Factor C Enhances Cervical Cancer Cell Invasiveness via Upregulation of Galectin-3 Protein. Gynecol Endocrinol, 30, 461-465. https://doi.org/10.3109/09513590.2014.898054
[28]
Punt, S., Thijssen, V.L., Vrolijk, J., de Kroon, C.D., Gorter, A., et al. (2015) Galectin-1, -3 and -9 Expression and Clinical Significance in Squamous Cervical Cancer. PLOS ONE, 10, e0129119. https://doi.org/10.1371/journal.pone.0129119
[29]
Castronovo, V., Van Den Brûle, F.A., Jackers, P., Clausse, N., Liu, F.T., et al. (1996) Decreased Expression of Galectin-3 Is Associated with Progression of Human Breast Cancer. The Journal of Pathology, 179, 43-48. https://doi.org/10.1002/(SICI)1096-9896(199605)179:1<43::AID-PATH541>3.0.CO;2-N
[30]
Meeusen, J.W., Johnson, J.N., Gray, A., Wendt, P., Jefferies, J.L., et al. (2015) Soluble ST2 and Galectin-3 in Pediatric Patients without Heart Failure. Clinical Biochemistry, 48, 1337-1340. https://doi.org/10.1016/j.clinbiochem.2015.08.007
Kouo, T., Huang, L., Pucsek, A.B., Cao, M., Solt, S., et al. (2015) Galectin-3 Shapes Antitumor Immune Responses by Suppressing CD8+ T Cells via LAG-3 and Inhibiting Expansion of Plasmacytoid Dendritic Cells. Cancer Immunology Research, 3, 412-423. https://doi.org/10.1158/2326-6066.CIR-14-0150
[33]
Lee, J.W., Song, S.Y., Choi, J.J., Choi, C.H., Kim, T.J., et al. (2006) Decreased Galectin-3 Expression during the Progression of Cervical Neoplasia. Journal of Cancer Research and Clinical Oncology, 132, 241-247. https://doi.org/10.1007/s00432-005-0069-1
[34]
Wang, Y., Liu, S., Tian, Y., Wang, Y., Zhang, Q., et al. (2018) Prognostic Role of Galectin-3 Expression in Patients with Solid Tumors: A Meta-Analysis of 36 Eligible Studies. Cancer Cell International, 18, Article No. 172. https://doi.org/10.1186/s12935-018-0668-y
[35]
Ziegler-Heitbrock, H.W., Stachel, D., Schlunk, T., Gurtler, L., Schramm, W., et al. (1988) Class II (DR) Antigen Expression on CD8+ Lymphocyte Subsets in Acquired Immune Deficiency Syndrome (AIDS). Journal of clinical Immunology, 8, 473-478. https://doi.org/10.1007/BF00916953
[36]
Tippalagama, R., Singhania, A., Dubelko, P., Lindestam Arlehamn, C.S., Crinklaw, A., et al. (2021) HLA-DR Marks Recently Divided Antigen-Specific Effector CD4 T Cells in Active Tuberculosis Patients. Journal of clinical Immunology, 207, 523-533 https://doi.org/10.4049/jimmunol.2100011
[37]
Saraiva, D.P., Jacinto, A., Borralho, P., Braga, S. and Cabral, M.G. (2018) HLA-DR in Cytotoxic T Lymphocytes Predicts Breast Cancer Patients’ Response to Neoadjuvant Chemotherapy. Front in Immunology, 9, Article 02605. https://doi.org/10.3389/fimmu.2018.02605
[38]
Tsuyama, S., Hashimoto, K., Nakamura, K., Tamura, H., Sasaki, K., et al. (1991) Different Behaviors in the Production and Release of SCC Antigen in Squamous-Cell Carcinoma. Tumour Biology, 12, 28-34. https://doi.org/10.1159/000217685
[39]
Sheu, B.C., Lin, R.H., Ho, H.N. and Huang, S.C. (1997) Down-Regulation of CD25 Expression on the Surface of Activated Tumor-Infiltrating Lymphocytes in Human Cervical Carcinoma. Human Immunology, 56, 39-48. https://doi.org/10.1016/S0198-8859(97)00111-0
[40]
Delgado, F.G., Martínez, E., Céspedes, M.A., Bravo, M.M., Navas, M.C., et al. (2009) Increase of Human Papillomavirus-16 E7-Specific T Helper Type 1 Response in Peripheral Blood of Cervical Cancer Patients after Radiotherapy. Immunology, 126, 523-534. https://doi.org/10.1111/j.1365-2567.2008.02912.x
[41]
Shalapour, S., Font-Burgada, J., Di Caro, G., Zhong, Z., Sanchez-Lopez, E., et al. (2015) Immunosuppressive Plasma Cells Impede T-Cell-Dependent Immunogenic Chemotherapy. Nature, 521, 94-98. https://doi.org/10.1038/nature14395
[42]
Wakita, D., Iwai, T., Harada, S., Suzuki, M., Yamamoto, K., et al. (2019) Cisplatin Augments Antitumor T-Cell Responses Leading to a Potent Therapeutic Effect in Combination with PD-L1 Blockade. Anticancer Research, 39, 1749-1760. https://doi.org/10.21873/anticanres.13281
