Oncotarget

Research Papers:

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

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

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Oncotarget. 2016; 7:43010-43026. https://doi.org/10.18632/oncotarget.9280

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Abstract

Stefano Garetto1,*, Claudia Sardi1,*, Elisa Martini1, Giuliana Roselli1, Diego Morone2, Roberta Angioni1, Beatrice Claudia Cianciotti1, Anna Elisa Trovato1, Davide Giuseppe Franchina1, Giovanni Francesco Castino3, Debora Vignali1, Marco Erreni3, Federica Marchesi3,4, Cristiano Rumio5 and Marinos Kallikourdis1,6

1 Adaptive Immunity Laboratory, Humanitas Clinical and Research Center, Rozzano (Milano), Italy

2 Humanitas Clinical and Research Center, Rozzano (Milano), Italy

3 Laboratory of Cellular Immunology, Humanitas Clinical and Research Center, Rozzano (Milano), Italy

4 Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy

5 Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy

6 Humanitas University, Rozzano (Milano), Italy

* These authors have contributed equally to this work

Correspondence to:

Marinos Kallikourdis, email:

Keywords: tumor, Adoptive Cell Therapy, T cells, chemokines, fibrosis

Received: September 13, 2015 Accepted: April 27, 2016 Published: May 10, 2016

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.


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