Tailored chemokine receptor modification improves homing of adoptive therapy T cells in a spontaneous tumor model.

Stefano Garetto,Claudia Sardi,Giuliana Roselli,Roberta Angioni,Davide Giuseppe Franchina,Cristiano Rumio,Beatrice Claudia Cianciotti,Elisa Martini,Giovanni Francesco Castino,Marco Erreni,Marinos Kallikourdis,Diego Morone,Debora Vignali,Anna Elisa Trovato,Federica Marchesi

doi:10.18632/oncotarget.9280

Stefano Garetto, Claudia Sardi + Show 13 more

Open Access

https://doi.org/10.18632/oncotarget.9280

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Journal: Oncotarget	Publication Date: May 10, 2016
Citations: 30	License type: cc-by

Affiliation: Humanitas University, University of Milan

Abstract

In recent years, tumor Adoptive Cell Therapy (ACT), using administration of ex vivo-enhanced T cells from the cancer patient, has become a promising therapeutic strategy. However, efficient homing of the anti-tumoral T cells to the tumor or metastatic site still remains a substantial hurdle. Yet the tumor site itself attracts both tumor-promoting and anti-tumoral immune cell populations through the secretion of chemokines. We attempted to identify these chemokines in a model of spontaneous metastasis, in order to “hijack” their function by expressing matching chemokine receptors on the cytotoxic T cells used in ACT, thus allowing us to enhance the recruitment of these therapeutic cells. Here we show that this enabled the modified T cells to preferentially home into spontaneous lymph node metastases in the TRAMP model, as well as in an inducible tumor model, E.G7-OVA. Due to the improved homing, the modified CD8+ T cells displayed an enhanced in vivo protective effect, as seen by a significant delay in E.G7-OVA tumor growth. These results offer a proof of principle for the tailored application of chemokine receptor modification as a means of improving T cell homing to the target tumor, thus enhancing ACT efficacy. Surprisingly, we also uncover that the formation of the peri-tumoral fibrotic capsule, which has been shown to impede T cell access to tumor, is partially dependent on host T cell presence. This finding, which would be impossible to observe in immunodeficient model studies, highlights possible conflicting roles that T cells may play in a therapeutic context.

Highlights

The current standard therapeutic strategy for primary cancer patients is surgical ablation and/or chemotherapy
We attempted to identify these chemokines in a model of spontaneous metastasis, in order to “hijack” their function by expressing matching chemokine receptors on the cytotoxic T cells used in Adoptive Cell Therapy (ACT), allowing us to enhance the recruitment of these therapeutic cells
Efficient adoptive cell therapy to combat established tumors depends upon a sufficient number of cytotoxic T cells, with high avidity for tumor antigen, reaching the tumor site without being dispersed in healthy tissue [14, 37]

Summary

Introduction

The current standard therapeutic strategy for primary cancer patients is surgical ablation and/or chemotherapy. Extensive research efforts are gradually shedding light into different mechanisms of local immunosuppression at the tumor site. These mechanisms, which range from immunosuppressive regulatory T cells (Treg) and Myeloid-Derived Suppressor cells to metabolic changes that inhibit cytotoxic T cell activity [2, 3], will have to www.impactjournals.com/oncotarget be overcome in order for the transferred CD8+ T cells to efficiently attack the tumor. There still remains a substantial hurdle in ensuring that the transferred anti-tumoral T cells physically reach and penetrate the tumor or metastatic site This relatively under-studied issue is likely to become a bottleneck in any cell-based therapeutic strategy [4]

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