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Synergistic effect of lymphotactin and interferon γ‐inducible protein‐10 transgene expression in T‐cell localization and adoptive T‐cell therapy of tumors
Author(s) -
Huang Hui,
Xiang Jim
Publication year - 2004
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.20043
Subject(s) - cd8 , adoptive cell transfer , cytotoxic t cell , cxcr3 , biology , t cell , granzyme b , microbiology and biotechnology , transgene , immunology , cancer research , chemokine , in vitro , antigen , immune system , chemokine receptor , biochemistry , gene
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‐γ 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. © 2004 Wiley‐Liss, Inc.