An efficient combination immunotherapy for antitumor immunity without accelerating cardiac allograft rejection.

Abstract

Immunotherapy with immune checkpoint inhibitors (ICIs), including antibodies against programmed cell death protein-1 (PD-1) and its receptor programmed cell death ligand-1 (PD-L1), represents a promising systematic treatment for advanced human malignancies. Transplantation remains the ultimate therapy for end-stage organ diseases. However, the efficacy of ICI treatment in solid organ transplant (SOT) recipients remains controversial. We established a transgenic primary liver cancer mouse model and performed allogeneic heterotopic heart transplantation. Different treatments were performed and survival curves were calculated. Graft samples were collected, and immune cells and the cell surface expression of PD-L1 were analysed by flow cytometry. Inflammatory cytokine levels in the serum were measured by an inflammatory array. The specificity of the histochemical techniques was tested by staining sections. A combination immunotherapy comprising a BET protein inhibitor (JQ1) and an immune checkpoint inhibitor (anti-PD-L1 antibody) was administered to primary liver cancer model mice bearing cardiac allografts. Interestingly, the combination immunotherapy effectively suppressed the progression of primary liver cancer but did not accelerate allograft rejection. In accordance with our previous findings, BET protein inhibition enhances the expression of a putative membrane transporter (Rab8A), which upregulates the expression of PD-L1 on the plasma membrane in a transgenic primary liver cancer mouse model. This may be a crucial mechanism of tumour progression arrest. Our data showed that heart transplantation upregulated the expression of the proinflammatory factor IFN-γ and suggested that BET protein inhibition (with JQ1) decreased PD-L1 expression in heart tissues after cardiac transplantation. This phenomenon was accompanied by enhanced infiltration of inflammatory IFN-γ. Our study provides a novel and efficient therapeutic strategy for SOT recipients.