Comparison of AAV/IL-7 Autocrine (T Cell) Versus Paracrine (DC) Gene Delivery for Enhancing CTL Stimulation and Function

Overview

Journal Cancer Immunol Immunother

Specialties Allergy & Immunology
Oncology
Pharmacology

Date 2010 Jan 22

PMID 20091029

Citations 4

Authors

Chang-Xuan You

Yong Liu

Min Shi

Maohua Cao

Rong-Cheng Luo

Paul L Hermonat

Affiliations

Soon will be listed here.

Abstract

Adoptive transfer of antigen-specific cytotoxic T lymphocyte (CTL) into patients holds promise in treating cancer. Such anti-cancer CTL are stimulated by professional antigen-presenting dendritic cells (DC). We hypothesize the gene delivery of various Th1-response cytokines, such as interleukin 7 (IL-7), should further enhance CTL stimulation and activity. However, the issue as to which cell type, DC (paracrine) or the T cell (autocrine), should express a particular Th1 cytokine gene for optimal CTL stimulation has never been addressed. We used adeno-associated virus-2 (AAV) to compare delivery of IL-7 and IL-2 genes into DC or T cells and to exogenous commercial cytokines for generating robust carcinoembryonic antigen (CEA)-specific CTL. AAV/IL-7 transduction of T cells (autocrine delivery) generated CTL with the highest killing capability. Consistent with this, AAV/IL-7 delivery generated T cell populations with the highest proliferation, highest interferon gamma expression, highest CD8(+):CD4(+) ratio, highest CD8(+), CD69(+) levels, and lowest CD4(+), CD25(+) (Treg) levels. These data are consistent with higher killing by the AAV/IL-7-altered CTL. These data strongly suggest that IL-7 autocrine gene delivery is optimal for CTL generation. These data also suggest Th1 cytokine autocrine versus paracrine delivery is an important issue for immuno-gene therapy and uncovers new questions into cytokine mechanism of action.

Citing Articles

AAV2/8-hSMAD3 gene delivery attenuates aortic atherogenesis, enhances Th2 response without fibrosis, in LDLR-KO mice on high cholesterol diet.

Zhu H, Cao M, Figueroa J, Cobos E, Uretsky B, Chiriva-Internati M J Transl Med. 2014; 12:252.

PMID: 25236373 PMC: 4189750. DOI: 10.1186/s12967-014-0252-8.

AAV2/IL-12 gene delivery into dendritic cells (DC) enhances CTL stimulation above other IL-12 applications: Evidence for IL-12 intracrine activity in DC.

You C, Shi M, Liu Y, Cao M, Luo R, Hermonat P Oncoimmunology. 2012; 1(6):847-855.

PMID: 23162752 PMC: 3489740. DOI: 10.4161/onci.20504.

HPV-16 E1, E2 and E6 each complement the Ad5 helper gene set, increasing rAAV2 and wt AAV2 production.

Cao M, Zhu H, Bandyopadhyay S, You H, Hermonat P Gene Ther. 2011; 19(4):418-24.

PMID: 21850053 PMC: 3220924. DOI: 10.1038/gt.2011.115.

Autocrine, not paracrine, interferon-gamma gene delivery enhances ex vivo antigen-specific cytotoxic T lymphocyte stimulation and killing.

Zhang D, Liu Y, Shi M, You C, Cao M, Luo R J Biomed Biotechnol. 2010; 2010:270985.

PMID: 20490265 PMC: 2871187. DOI: 10.1155/2010/270985.

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