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

// Stefano Garetto 1,* , Claudia Sardi 1,* , Elisa Martini 1 , Giuliana Roselli 1 , Diego Morone 2 , Roberta Angioni 1 , Beatrice Claudia Cianciotti 1 , Anna Elisa Trovato 1 , Davide Giuseppe Franchina 1 , Giovanni Francesco Castino 3 , Debora Vignali 1 , Marco Erreni 3 , Federica Marchesi 3,4 , Cristiano Rumio 5 and Marinos Kallikourdis 1,6 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, Universita degli Studi di Milano, Milan, Italy 5 Dipartimento di Scienze Farmacologiche e Biomolecolari, Universita 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.