Synergistic effect of lymphotactin and interferon gamma-inducible protein-10 transgene expression in T-cell localization and adoptive T-cell therapy of tumors.
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.
Huang
Hui
H
Research Unit, Saskatchewan Cancer Agency, Department of Microbiology, University of Saskatchewan, Saskatoon, Canada.
Xiang
Jim
J
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002455:Cell Division; D054357:Chemokine CXCL10; D019744:Chemokines, C; D019743:Chemokines, CXC / Q000235:genetics*; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018014:Gene Transfer Techniques; D016219:Immunotherapy, Adoptive; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000473:pathology; D008222:Lymphokines / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009369:Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D010047:Ovalbumin / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012795:Sialoglycoproteins / Q000235:genetics*; D019076:Transgenes; D014407:Tumor Cells, Cultured
D054357:Chemokine CXCL10; D019744:Chemokines, C; D019743:Chemokines, CXC; D008222:Lymphokines; D011948:Receptors, Antigen, T-Cell; D012795:Sialoglycoproteins; C486249:Xcl1 protein, mouse; C018997:lymphotactin; D010047:Ovalbumin