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PPARδ inhibition blocks tumor-induced Bregs and enhances CD40 agonist immunotherapy

ABSTRACT: Most cancers are cold tumors characterized by a lack of effector T cells and hence unresponsive to immune checkpoint blockades, highlighting the importance of repairing the failed T cell priming in cancer immunotherapy. CD40 agonists are efficient in eliciting T cell responses and effective in converting cold tumors into hot, their clinical application, however, is limited by the very narrow window between the effective and toxic dosages. Here, we sought to reduce the effective dosage of CD40 agonists by combination therapy. We identified a CD19+CD24hiCD38lowIgDlow/- regulatory B cell (Breg) subset that is increased in tumor-bearing mice and cancer patients, and discovered that PPARδ is highly expressed in these tumor-associated Bregs and required for their proliferation and function. Inhibition of PPARδ acted synergistically with agonist anti-CD40 to enhance antitumor immunity without increasing toxicity in murine melanoma and bladder carcinoma models. Combination therapy with PPARδ inhibitor could reduce anti-CD40 dosage by over 60% to a well-tolerated level with improved or at least not compromised antitumor effects, providing a potential strategy for safely using CD40 agonists in cancer treatment. PPARδ also offers a new target for selectively blocking Breg activity while sparing immunostimulatory B cells that are known to aid antitumor immunotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE168523 | GEO | 2024/02/20

REPOSITORIES: GEO

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