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 H ，Xiang J 《INTERNATIONAL JOURNAL OF CANCER》

Combined CD4+ Th1 effect and lymphotactin transgene expression enhance CD8+ Tc1 tumor localization and therapy.

Huang H ，Bi XG ，Yuan JY ，Xu SL ，Guo XL ，Xiang J ... -  《GENE THERAPY》

Synergistic enhancement of antitumor immunity with adoptively transferred tumor-specific CD4+ and CD8+ T cells and intratumoral lymphotactin transgene expression.

Huang H ，Li F ，Gordon JR ，Xiang J ... -  《CANCER RESEARCH》

Synergistic effect of adoptive T-cell therapy and intratumoral interferon gamma-inducible protein-10 transgene expression in treatment of established tumors.

Huang H ，Liu Y ，Xiang J 《CELLULAR IMMUNOLOGY》

Lymphotactin gene-modified bone marrow dendritic cells act as more potent adjuvants for peptide delivery to induce specific antitumor immunity.

Cao X ，Zhang W ，He L ，Xie Z ，Ma S ，Tao Q ，Yu Y ，Hamada H ，Wang J ... -  《JOURNAL OF IMMUNOLOGY》