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Copyright © 2022 S. González-Ochoa et al. This is an open access article distributed under the Creative Commons Attribution License (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. https://creativecommons.org/licenses/by/4.0/

Abstract

Background/Aims. Prostate cancer (PCa) is one of the neoplasms with the highest incidence and mortality rate in men worldwide. Advanced stages of the disease are usually very aggressive, and most are treated with chemotherapeutic drugs that generally cause side effects in these patients. However, additional therapeutic targets such as the IL6R/STAT-3 axis and TIGIT have been proposed, mainly due to their relevance in the development of PCa and regulation of NK cell-mediated cytotoxicity. Here, we evaluate the effect of inhibitors directed against these therapeutic targets primarily via an analysis of NK cell function versus prostate cancer cells. Methods. We analyzed the secretion of cytokines, chemokines, and growth factors in 22Rv1, LNCaP, and DU145 cells. In these cells, we also evaluated the expression of NK ligands, IL6R, STAT-3, and phosporylated STAT-3. In NK-92 cells, we evaluated the effects of Stattic (Stt) and tocilizumab (Tcz) on NK receptors. In addition, we assessed if the disruption of the IL6R/STAT-3 pathway and blockade of TIGIT potentiated the cytotoxicity of NK-92 cells versus DU145 cells. Results. DU145 abundantly secretes M-CSF, VEGF, IL-6, CXCL8, and TGF-β. Furthermore, the expression of CD155 was found to increase in accordance with aggressiveness and metastatic status in the prostate cancer cells. Stt and Tcz induce a decrease in STAT-3 phosphorylation in the DU145 cells and, in turn, induce an increase of NKp46 and a decrease of TIGIT expression in NK-92 cells. Finally, the disruption of the IL6R/STAT-3 axis in prostate cancer cells and the blocking of TIGIT on NK-92 were observed to increase the cytotoxicity of NK-92 cells against DU145 cells through an increase in sFasL, granzyme A, granzyme B, and granulysin. Conclusions. Our results reveal that the combined use of inhibitors directed against the IL6R/STAT-3 axis and TIGIT enhances the functional activity of NK cells against castration-resistant prostate cancer cells.

Details

Title
Combination Blockade of the IL6R/STAT-3 Axis with TIGIT and Its Impact on the Functional Activity of NK Cells against Prostate Cancer Cells
Author
González-Ochoa, S 1 ; Tellez-Bañuelos, M C 2   VIAFID ORCID Logo  ; Méndez-Clemente, A S 1 ; Bravo-Cuellar, A 3 ; G Hernández Flores 4 ; Palafox-Mariscal, L A 1 ; Haramati, J 2 ; Pedraza-Brindis, E J 5 ; Sánchez-Reyes, K 6 ; Ortiz-Lazareno, P C 1   VIAFID ORCID Logo 

 Instituto Mexicano del Seguro Social (IMSS), Centro de Investigación Biomédica de Occidente (CIBO), División de Inmunología, Guadalajara, 44340, Jalisco, Mexico; Universidad de Guadalajara, Centro Universitario de Ciencias de la Salud (CUCS), Programa de Doctorado en Ciencias Biomédicas Orientación Inmunología, Guadalajara, 44340, Jalisco, Mexico 
 Universidad de Guadalajara, Centro Universitario de Ciencias de la Salud (CUCS), Programa de Doctorado en Ciencias Biomédicas Orientación Inmunología, Guadalajara, 44340, Jalisco, Mexico; Universidad de Guadalajara, Centro Universitario de Ciencias Biológicas y Agropecuarias (CUCBA), Departamento de Biología Celular y Molecular, Las Agujas, 45220, Jalisco, Mexico 
 Instituto Mexicano del Seguro Social (IMSS), Centro de Investigación Biomédica de Occidente (CIBO), División de Inmunología, Guadalajara, 44340, Jalisco, Mexico; Universidad de Guadalajara, Centro Universitario de los Altos (CUALTOS), Departamento de Ciencias de la Salud, Tepatitlán de Morelos, 47620, Jalisco, Mexico 
 Instituto Mexicano del Seguro Social (IMSS), Centro de Investigación Biomédica de Occidente (CIBO), División de Inmunología, Guadalajara, 44340, Jalisco, Mexico 
 Universidad de Guadalajara, Centro Universitario de Ciencias de la Salud (CUCS), HIV and Immunodeficiencies Research Institute, Clinical Medicine Department, Guadalajara, 44280, Jalisco, Mexico; Universidad Autónoma de Guadalajara, Departamento Académico de Aparatos y Sistemas I, Unidad Académica de Ciencias de la Salud, Zapopan, 45129, Jalisco, Mexico 
 Universidad de Guadalajara, Centro Universitario de Ciencias de la Salud (CUCS), HIV and Immunodeficiencies Research Institute, Clinical Medicine Department, Guadalajara, 44280, Jalisco, Mexico 
Editor
Shengjun Wang
Publication year
2022
Publication date
2022
Publisher
John Wiley & Sons, Inc.
ISSN
23148861
e-ISSN
23147156
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2653906808
Copyright
Copyright © 2022 S. González-Ochoa et al. This is an open access article distributed under the Creative Commons Attribution License (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. https://creativecommons.org/licenses/by/4.0/