Synergistic effect of lymphotactin and interferon gamma-inducible protein-10 transgene expression in T-cell localization and adoptive T-cell therapy of tumors.

Abstract

The lack of efficient T-cell infiltration of tumors is a major obstacle to successful adoptive T-cell therapy. We have previously demonstrated that adenovirus (AdV)-mediated transgene lymphotactin (Lptn) or IP-10 expression in tumors can significantly enhance T-cell tumor infiltration. In this study, active OVA-specific CD8+ T cells were prepared by coculturing naive OVA-specific CD8+ T cells from transgenic OT I mice with OVA-I peptide-pulsed dendritic cells in vitro. These XCR-1- and CXCR3-expressing T cells predominantly secreted IFN-gamma and displayed significant killing activity (84% at effector:target cell ratio of 1.5) against OVA-expressing EG7 tumor cells through perforin-mediated pathway. Our data also showed that chemokine Lptn and IP-10 not only can chemoattract, but also stimulate proliferation of CD8+ T cells in vitro, and that a mixture of Lptn and IP-10 can more efficiently chemoattract CD8+ T cells than either one of them. Furthermore, we demonstrated that the transferred CD8+ T cells detected in group of tumors treated with both AdVLptn and AdVIP-10 (group a) are around 4 and 2 times more than that in groups of tumors treated with control AdVpLpA (group b) and either AdVIP-10 (group c) or AdVLptn (group d), respectively. Around 87.5% of mice in group a were tumor-free compared to the aggressive tumor growth in all 8 mice of group b and 25% or 37.5% cured mice seen in groups c and d (p<0.05). Thus, our results indicate that enhancement of adoptive T-cell therapy can be obtained by double tranmsgene Lptn and IP-10 expression, which facilitates CD8+ T-cell tumor localization through proliferation and chemoattraction of the transferred CD8+ T cells by in situ chemokine transgene expressions in the tumors. Collectively, our data provide solid evidence of a potent synergy between adoptive T-cell therapy and adenovirus-mediated Lptn and IP-10 gene transfer into tumor tissues, which culminated in the T-cell tumor localization and eradication of well-established tumor masses.

• Authors: Hui Huang, Jim Xiang
• Journal: International journal of cancer (Int J Cancer) Vol. 109 Issue 6 Pg. 817-25 (May 10 2004) ISSN: 0020-7136 [Print] United States
• PMID: 15027114 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2004 Wiley-Liss, Inc.

Chemical References

• Chemokine CXCL10
• Chemokines, C
• Chemokines, CXC
• Lymphokines
• Receptors, Antigen, T-Cell
• Sialoglycoproteins
• Xcl1 protein, mouse
• lymphotactin
• Ovalbumin

Topics

• Adenoviridae (genetics)
• Animals
• CD8-Positive T-Lymphocytes (immunology)
• Cell Division
• Chemokine CXCL10
• Chemokines, C
• Chemokines, CXC (genetics)
• Chemotaxis, Leukocyte (immunology)
• Cytotoxicity, Immunologic
• Dendritic Cells (immunology)
• Drug Synergism
• Female
• Gene Expression Regulation, Neoplastic
• Gene Transfer Techniques
• Immunotherapy, Adoptive
• Lymphocyte Activation
• Lymphocytes, Tumor-Infiltrating (immunology, pathology)
• Lymphokines (genetics)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Neoplasms (immunology, pathology, therapy)
• Ovalbumin (immunology)
• Receptors, Antigen, T-Cell (genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Sialoglycoproteins (genetics)
• Transgenes
• Tumor Cells, Cultured