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PPARδ inhibition blocks the induction and function of tumor-induced IL-10+ regulatory B cells and enhances cancer immunotherapy

IL-10+ regulatory B cells (Bregs) play a significant role in cancer immunotherapy and their presence is an indicator of negative outcome. We found that PPARδ is significantly upregulated in tumor-induced IL-10+ Bregs with a phenotype of CD19+CD24hiIgDlo/-CD38lo or CD19+CD24hiIgDlo/-CD38hi in both mice and humans, and the level of PPARδ expression was correlated with their potential to produce IL-10 and to inhibit T cell activation. Genetic inactivation of PPARδ in B cells impaired the development and function of IL-10+ B cells, and treatment with PPARδ inhibitor diminished the induction of IL-10+ Bregs by tumor and CD40 engagement. Importantly, immunotherapy with anti-CD40 or anti-PD1 antibody achieved a markedly improved outcome in tumor-bearing mice with PPARδ deficiency in B cells or treated with PPARδ inhibitor. This study shows that PPARδ is required for the development and function of IL-10+ Bregs, providing a new and effective target for selectively blocking Bregs and improving antitumor immunotherapy.

 

Comments:

The passage you provided describes a study that investigates the role of IL-10+ regulatory B cells (Bregs) in cancer immunotherapy and their association with PPARδ expression. Here's a summary of the key findings:

1. Significance of IL-10+ Bregs: IL-10+ Bregs have a notable impact on cancer immunotherapy outcomes, and their presence is associated with negative outcomes.

2. Upregulation of PPARδ in tumor-induced IL-10+ Bregs: The study observed a significant increase in the expression of PPARδ in IL-10+ Bregs stimulated by tumors in both mice and humans.

3. Correlation between PPARδ expression and IL-10 production: The level of PPARδ expression correlated with the ability of IL-10+ Bregs to produce IL-10 and inhibit T cell activation.

4. Genetic inactivation and inhibition of PPARδ: Inactivating PPARδ in B cells impaired the development and function of IL-10+ Bregs. Additionally, treatment with a PPARδ inhibitor reduced the induction of IL-10+ Bregs by tumors and CD40 engagement.

5. Improved outcomes with PPARδ deficiency or inhibition: Tumor-bearing mice with deficient PPARδ in B cells or treated with a PPARδ inhibitor showed significantly improved outcomes when subjected to immunotherapy with anti-CD40 or anti-PD1 antibodies.

In summary, this study highlights the importance of PPARδ in the development and function of IL-10+ Bregs. Targeting PPARδ could provide a promising approach for selectively blocking Bregs and enhancing the effectiveness of antitumor immunotherapy.

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S8960 CD38 inhibitor 1 (compound 78c) CD38 inhibitor 1 (compound 78c, CD38-IN-78c, MDK-7553) is a potent inhibitor of CD38 with IC50 of 7.3 nM and 1.9 nM for human CD38 and mouse CD38, respetively.

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