Nonlysosomal Route of mRNA Delivery and Combining with Epigenetic Regulation Optimized Antitumor Immunoprophylactic Efficacy

Abstract

Currently, mRNA-based tumor therapies are in full flow because in vitro-transcribed (IVT) mRNA has the potential to express tumor antigens to initiate the adaptive immune responses. However, the efficacy of such therapy relies heavily on the delivery system. Here, a pardaxin-modified liposome loaded with tumor antigen-encoding mRNA and adjuvant (2ʹ,3ʹ-cGAMP, (cyclic [G(2ʹ,5ʹ)pA(3ʹ,5ʹ)p])), termed P-Lipoplex-CDN is reported. Due to an nonlysosomal delivery route, the transfection efficiency on dendritic cells (DCs) is improved by reducing the lysosome disruption of cargos. The mRNA modified DCs efficiently induce tumor antigen-specific immune responses both in vitro and in vivo. As prophylactic vaccines, mRNA transfected DCs significantly delay the occurrence and development of tumors, and several immunized mice are even completely resistant to tumors. Interestingly, the efficacy depends on the major histocompatibility complex class I (MHC-I) expression level on tumor cells. Furthermore, epigenetic modification (decitabine, DAC) is applied as a combination strategy to deal with malignant tumor progression caused by deficient tumor MHC-I expression. This study highlights the close relationship between mRNA-DCs vaccine efficacy and the expression level of tumor cell MHC-I molecules. Moreover, a feasible strategy for tumor MHC-I expression deficiency is proposed, which may provide clinical guidance for the design and application of mRNA-based tumor therapies.

Liposome Vaccine for Active Regulation of Cellular and Humoral Immunity

“…DSPE-PEG-Man and DSPE-PEG-Par were synthesized by a coupled reaction of DSPE-PEG-NH 2 and mannopyranosylphenyl isothiocyanate or pardaxin peptide, as reported. − Then, S protein- and CpG-loaded LIPO with or without APC (or) and ER targeting was then prepared, named S + CpG@Man-LIPO, S + CpG@Par-LIPO, S + CpG@PM-LIPO, and S + CpG@LIPO. Blank LIPO and PM-LIPO without loading drugs were prepared as a control.…”

mRNA Cancer Vaccines: Construction and Boosting Strategies

“…In a study, Liu et al reported a combination therapeutic strategy that used decitabine in combination with pardaxin-modified liposomes loading with tumor antigenencoding mRNA and adjuvant (2′,3′-cGAMP) for in vitro transfection of DCs and preparation of mRNA-DC vaccines. 200 The results showed that such combination therapy improved mRNA transfection efficiency while enhancing the maturation of DCs, and the mRNA-DC-based tumor vaccines also showed amplified immune responses under low-dose mRNA administration. Importantly, mRNA-DC tumor vaccines in combination with decitabine sensitized the efficacy of mRNA-DC vaccines by restoring the expression of MHC-I in the tumor cells.…”

Rethinking Antigen Source: Cancer Vaccines Based on Whole Tumor Cell/tissue Lysate or Whole Tumor Cell

“…[150] Considering that the clin- ical efficacy of cancer vaccines based on pre-determined neoantigens is limited due to the lack of broadly expressed tumor antigens among cancer cells and the risk of immune escape in treatments targeting single antigens, autologous tumor cells are used for preparing individualized tumor vaccines for inducing polyclonal T cell responses. [151] Applying whole-cancer cells as cancer vaccines could help overcome the limitations of cancer vaccines based on several selected neoantigens. However, when applying whole-cancer cell as cancer vaccines, it is necessary to ensure that all cancer cells are nonviable.…”

“…[ 150 ] Considering that the clinical efficacy of cancer vaccines based on pre‐determined neoantigens is limited due to the lack of broadly expressed tumor antigens among cancer cells and the risk of immune escape in treatments targeting single antigens, autologous tumor cells are used for preparing individualized tumor vaccines for inducing polyclonal T cell responses. [ 151 ]…”