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Combination Blockade of the IL6R/STAT-3 Axis with TIGIT and Its Impact on the Functional Activity of NK Cells against

S González-Ochoa1,2, M C Tellez-Bañuelos2,3, A S Méndez-Clemente1,2

  • 1Instituto Mexicano del Seguro Social (IMSS), Centro de Investigación Biomédica de Occidente (CIBO), División de Inmunología, Guadalajara, 44340, Jalisco, Mexico.

Journal of Immunology Research
|April 25, 2022
PubMed
Abstract

Insights

Combining IL6R/STAT-3 pathway inhibitors with TIGIT blockade enhances natural killer (NK) cell activity against prostate cancer. This approach boosts NK cell cytotoxicity, offering a promising strategy for treating castration-resistant prostate cancer.

Area of Science:

  • Immunology
  • Oncology
  • Cell Biology

Background:

  • Prostate cancer, particularly castration-resistant forms, presents significant therapeutic challenges.
  • Natural killer (NK) cells are crucial for innate immunity and cancer surveillance.
  • Understanding the interplay between cancer cells and NK cells is vital for developing novel immunotherapies.

Purpose of the Study:

  • To analyze cytokine and chemokine secretion in prostate cancer cell lines (22Rv1, LNCaP, DU145).
  • To evaluate NK ligand expression and the IL6R/STAT-3 pathway in these cells.
  • To assess the impact of IL6R/STAT-3 pathway disruption and TIGIT blockade on NK-92 cell cytotoxicity against DU145 cells.

Main Methods:

  • Analyzed cytokine/chemokine secretion and NK ligand expression in prostate cancer cell lines.
  • Investigated the effects of Stattic and tocilizumab on NK receptors in NK-92 cells.
  • Assessed the potentiation of NK-92 cell cytotoxicity against DU145 cells by disrupting the IL6R/STAT-3 pathway and blocking TIGIT.

Main Results:

  • DU145 cells secrete M-CSF, VEGF, IL-6, CXCL8, and TGF-β; CD155 expression correlates with cancer aggressiveness.
  • Stattic and tocilizumab decreased STAT-3 phosphorylation in DU145 cells, increasing NKp46 and decreasing TIGIT expression in NK-92 cells.
  • Disrupting the IL6R/STAT-3 axis and blocking TIGIT increased NK-92 cytotoxicity against DU145 cells via enhanced sFasL, granzyme A, granzyme B, and granulysin.

Conclusions:

  • Combined inhibition of the IL6R/STAT-3 axis and TIGIT blockade significantly enhances NK cell functional activity.
  • This combination therapy demonstrates increased cytotoxicity against castration-resistant prostate cancer cells.
  • Targeting both pathways represents a promising strategy for improving immunotherapy outcomes in prostate cancer.

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