Journal Article

A DNA vaccine expressing an optimized secreted FAPα induces enhanced anti-tumor activity by altering the tumor microenvironment in a murine model of breast cancer

Geng, Fei, Guo, Jie, Dong, Ling, Liu, Chen-Lu, Guo, Qian-Qian, Yu, Xiang-Hui, Wu, Hui, Xie, Yu, Kong, Wei, Wu, Jia-Xin, Zhou, Yi, Yu, Bin, Zhang, Hai-Hong

2019

Overview

•An optimized FAPα-targeted DNA vaccine was constructed.•DNA sequence homology between optimized FAPα and original FAPα was only 76%.•The vaccine induced more FAPα-specific CD8+ T cells.•Clearance of CAFs decreased the infiltration of MDSCs in tumor.•Mouse FAPα vaccine and human FAPα vaccine had similar anti-tumor effects. Cancer-associated fibroblasts (CAFs), major components of the tumor microenvironment (TME), promote tumor growth and metastasis and inhibit the anti-tumor immune response. We previously constructed a DNA vaccine expressing human FAPα, which is highly expressed by CAFs, to target these cells in the TME, and observed limited anti-tumor effects in the 4T1 breast cancer model. When the treatment time was delayed until tumor nodes formed, the anti-tumor effect of the vaccine completely disappeared. In this study, to improve the safety and efficacy, we constructed a new FAPα-targeted vaccine containing only the extracellular domain of human FAPα with a tissue plasminogen activator signal sequence for enhanced antigen secretion and immunogenicity. The number of CAFs was more effectively reduced by CD8+ T cells induced by the new vaccine. This resulted in decreases in CCL2 and CXCL12 expression, leading to a significant decrease in the ratio of myeloid-derived suppressor cells in the TME. Moreover, when mice were treated after the establishment of tumors, the vaccine could still delay tumor growth. To facilitate the future application of the vaccine in clinical trials, we further optimized the gene codons and reduced the homology between the vaccine and the original sequence, which may be convenient for evaluating the vaccine distribution in the human body. These results indicated that the new FAPα-targeted vaccine expressing an optimized secreted human FAPα induced enhanced anti-tumor activity by reducing the number of FAPα+ CAFs and enhancing the recruitment of effector T cells in the 4T1 tumor model mice.

• Publisher: Elsevier Ltd,Elsevier Limited
• Subject: Allergy and Immunology / Amino acids / Animal models / Anticancer properties / Antigens / antineoplastic activity / Antitumor agents / Breast cancer / breast neoplasms / Cancer immunotherapy / Cancer therapies / Cancer-associated fibroblast / CD8 antigen / CD8-positive T-lymphocytes / chemokine CCL2 / chemokine CXCL12 / Chemotherapy / Clinical trials / Codons / CXCL12 protein / Deoxyribonucleic acid / DNA / DNA vaccine / DNA vaccines / Effector cells / FAPα / Fibroblasts / Homology / humans / Immune response / Immune system / Immunogenicity / Immunotherapy / Laboratory animals / Lymphocytes / Lymphocytes T / Medical research / Metastases / Metastasis / mice / Monocyte chemoattractant protein 1 / Mutation / Myeloid-derived suppressor cell / Plasmids / recombinant vaccines / Science / secretion / signal peptide / Suppressor cells / t-Plasminogen activator / Tumors / Tumour microenvironment / Vaccines