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

Chen Chen; Jianan Ma; Chenchen Pi; Wei Huang; Tao Zhang; Cong Fu; Wentao Liu; Yong-Guang Yang

doi:10.1038/s41421-023-00568-6

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

Cell Discov. 2023 Jun 8;9(1):54. doi: 10.1038/s41421-023-00568-6.

Authors

Chen Chen^#^{1

2

3}, Jianan Ma^#^{1

2}, Chenchen Pi^{1

2}, Wei Huang^{1

2}, Tao Zhang^{1

2}, Cong Fu^{1

2}, Wentao Liu^{4

5}, Yong-Guang Yang^{6

7

8}

Affiliations

¹ Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, Jilin, China.
² National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Jilin University, Changchun, Jilin, China.
³ Centre of Oncology, The First Hospital of Jilin University, Changchun, Jilin, China.
⁴ Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, Jilin, China. liuwt@jlu.edu.cn.
⁵ National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Jilin University, Changchun, Jilin, China. liuwt@jlu.edu.cn.
⁶ Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, Jilin, China. yongg@jlu.edu.cn.
⁷ National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Jilin University, Changchun, Jilin, China. yongg@jlu.edu.cn.
⁸ International Center of Future Science, Jilin University, Changchun, Jilin, China. yongg@jlu.edu.cn.

^# Contributed equally.

Abstract

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⁺CD24^hiIgD^lo/-CD38^lo or CD19⁺CD24^hiIgD^lo/-CD38^hi 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.

Abstract

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