Clofazimine enhances anti-PD-1 immunotherapy in glioblastoma by inhibiting Wnt6 signaling and modulating the tumor immune microenvironment.

in Cancer immunology, immunotherapy : CII by Yuze Zhao, Yuguang Song, Weiping Li, Jiangping Wu, Zhengbao Zhao, Tingli Qu, Hong Xiao, Manyuan Wang, Min Zhu, Peiming Zheng, Huili Wan, Qingkun Song, Huixia Zheng, Shuo Wang

TLDR

  • The study demonstrates that combining clofazimine with anti-PD-1 therapy significantly reduces tumor growth and extends survival in GBM mouse models, suggesting a promising new therapeutic approach for this aggressive brain tumor.
  • The findings indicate that clofazimine enhances the efficacy of anti-PD-1 immunotherapy by modulating the Wnt6/β-catenin/PD-L1 axis and reshaping the immune microenvironment.

Abstract

Glioblastoma multiforme (GBM) is an aggressive and lethal primary brain tumor with limitedtreatment options due to its resistance to conventional therapies and an immunosuppressive tumor microenvironment. In this study, we investigated whether clofazimine, an inhibitor of the Wnt/β-catenin signaling pathway, could enhance the efficacy of anti-PD-1 immunotherapy in GBM. Our in vitro and in vivo experiments demonstrated that clofazimine suppressed GBM cell proliferation, induced apoptosis, and inhibited invasion by downregulating Wnt6-mediated activation of the Wnt/β-catenin pathway and the downstream MEK/ERK signaling cascade, leading to decreased PD-L1 expression. Notably, the combination of clofazimine and anti-PD-1 therapy significantly reduced tumor growth and intracranial invasion in orthotopic GBM mouse models, resulting in extended survival. This combination therapy also reshaped the tumor immune microenvironment by increasing cytotoxic CD8T cell infiltration, reducing regulatory T cells, and promoting T cell receptor clonality and diversity, indicative of a robust anti-tumor immune response. Our findings suggest that clofazimine enhances the therapeutic effects of anti-PD-1 immunotherapy in GBM through modulation of the Wnt6/β-catenin/PD-L1 axis and reshaping the immune microenvironment. While these results are promising, further clinical studies are needed to evaluate the efficacy and safety of this combinatory approach in GBM patients.

Overview

  • The study investigates whether clofazimine, an inhibitor of the Wnt/β-catenin signaling pathway, can enhance the efficacy of anti-PD-1 immunotherapy in Glioblastoma multiforme (GBM).
  • In vitro and in vivo experiments demonstrated that clofazimine suppressed GBM cell proliferation, induced apoptosis, and inhibited invasion by downregulating Wnt6-mediated activation of the Wnt/β-catenin pathway and the downstream MEK/ERK signaling cascade.
  • The primary objective of the study is to evaluate the combination of clofazimine and anti-PD-1 therapy as a potential treatment for GBM, a highly aggressive and lethal primary brain tumor.

Comparative Analysis & Findings

  • The study showed that the combination of clofazimine and anti-PD-1 therapy significantly reduced tumor growth and intracranial invasion in orthotopic GBM mouse models, resulting in extended survival.
  • Compared to anti-PD-1 therapy alone, the combination therapy with clofazimine led to increased cytotoxic CD8 T cell infiltration, reduced regulatory T cells, and promoted T cell receptor clonality and diversity, indicative of a robust anti-tumor immune response.
  • The study demonstrated that clofazimine enhances the therapeutic effects of anti-PD-1 immunotherapy in GBM through modulation of the Wnt6/β-catenin/PD-L1 axis and reshaping the immune microenvironment.

Implications and Future Directions

  • The study suggests that clofazimine may be a promising adjuvant therapy to enhance the efficacy of anti-PD-1 immunotherapy in GBM, but further clinical studies are needed to evaluate the efficacy and safety of this combinatory approach in GBM patients.
  • Future studies can explore the optimal dosing and combination regimens of clofazimine and anti-PD-1 therapy to maximize the therapeutic benefits and minimize potential side effects.
  • The study highlights the importance of understanding the immune microenvironment and the role of the Wnt/β-catenin signaling pathway in resistance to anti-PD-1 therapy, which could lead to the development of new therapeutic strategies for GBM.
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