Combination of epigenetic regulation with gene therapy-mediated immune checkpoint blockade induces anti-tumour effects and immune response in vivo

Huapan Fang,Lin Lin,Yingying Hu,Jie Chen,Xuesi Chen,Huayu Tian,Yanhui Li,Zhaopei Guo

doi:10.1038/s41467-021-27078-x

Abstract

Immunotherapy has become a powerful cancer treatment, but only a small fraction of patients have achieved durable benefits due to the immune escape mechanism. In this study, epigenetic regulation is combined with gene therapy-mediated immune checkpoint blockade to relieve this immune escape mechanism. PPD (i.e., mPEG-b-PLG/PEI-RT3/DNA) is developed to mediate plasmid-encoding shPD-L1 delivery by introducing multiple interactions (i.e., electrostatic, hydrogen bonding, and hydrophobic interactions) and polyproline II (PPII)-helix conformation, which downregulates PD-L1 expression on tumour cells to relieve the immunosuppression of T cells. Zebularine (abbreviated as Zeb), a DNA methyltransferase inhibitor (DNMTi), is used for the epigenetic regulation of the tumour immune microenvironment, thus inducing DC maturation and MHC I molecule expression to enhance antigen presentation. PPD plus Zeb combination therapy initiates a systemic anti-tumour immune response and effectively prevents tumour relapse and metastasis by generating durable immune memory. This strategy provides a scheme for tumour treatment and the inhibition of relapse and metastasis.

Highlights

Immunotherapy has become a powerful cancer treatment, but only a small fraction of patients have achieved durable benefits due to the immune escape mechanism
Important is that T cells have immune checkpoint-dependent immunosuppression, e.g., programmed cell death 1 (PD-1) receptor expressed on T cells binds to its two ligands, PD-1 ligand 1 (PD-L1) and ligand 2 (PD-L2), which are upregulated on tumour cells
major histocompatibility complex (MHC) I molecules (HLA-A and HLA-B) and cancer testis antigen (CTA) genes (SSX-1, SSX-2, SSX-4, SSX-5, and MAGE-1) were remarkably upregulated after PPD plus Zeb treatment. These results suggested that PPD plus Zeb combination therapy downregulated PD-L1 expression on tumour cells to relieve the immunosuppression of T cells, and induced the enhancement of MHC I molecules on tumour cells via CTA, thereby mounting the visibility of tumour cells to the adaptive immune system in a humanized mouse model

Summary

Introduction

Immunotherapy has become a powerful cancer treatment, but only a small fraction of patients have achieved durable benefits due to the immune escape mechanism. PPD plus Zeb combination therapy initiates a systemic anti-tumour immune response and effectively prevents tumour relapse and metastasis by generating durable immune memory. This strategy provides a scheme for tumour treatment and the inhibition of relapse and metastasis. It has been reported that epigenetic therapy such as DNA methyltransferase inhibitors (DNMTi) could upregulate the expression of tumour-associated antigens and induce the enhancement of major histocompatibility complex (MHC) class I molecules on tumour cells via cancer testis antigen (CTA), thereby mounting the visibility of tumour cells to the adaptive immune system[23,24,25,26]. Gene therapy-guided immune checkpoint blockade could be used as an alternative strategy of reversing T-cell exhaustion while avoiding the side effects caused by PD-1/PD-L1-

Methods

Results

Conclusion