title: Tailored chemokine receptor modification improves homing of adoptive therapy T cells in a spontaneous tumor model.
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.
authors.affiliation: Adaptive Immunity Laboratory, Humanitas Clinical and Research Center, Rozzano (Milano), Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Garetto
authors.affiliation: Adaptive Immunity Laboratory, Humanitas Clinical and Research Center, Rozzano (Milano), Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Sardi
authors.affiliation: Adaptive Immunity Laboratory, Humanitas Clinical and Research Center, Rozzano (Milano), Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Martini
authors.affiliation: Adaptive Immunity Laboratory, Humanitas Clinical and Research Center, Rozzano (Milano), Italy.
authors.forename: Giuliana
authors.initials: G
authors.lastname: Roselli
authors.affiliation: Humanitas Clinical and Research Center, Rozzano (Milano), Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Morone
authors.affiliation: Adaptive Immunity Laboratory, Humanitas Clinical and Research Center, Rozzano (Milano), Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Angioni
authors.affiliation: Adaptive Immunity Laboratory, Humanitas Clinical and Research Center, Rozzano (Milano), Italy.
authors.forename: Beatrice Claudia
authors.initials: BC
authors.lastname: Cianciotti
authors.affiliation: Adaptive Immunity Laboratory, Humanitas Clinical and Research Center, Rozzano (Milano), Italy.
authors.forename: Anna Elisa
authors.initials: AE
authors.lastname: Trovato
authors.affiliation: Adaptive Immunity Laboratory, Humanitas Clinical and Research Center, Rozzano (Milano), Italy.
authors.forename: Davide Giuseppe
authors.initials: DG
authors.lastname: Franchina
authors.affiliation: Laboratory of Cellular Immunology, Humanitas Clinical and Research Center, Rozzano (Milano), Italy.
authors.forename: Giovanni Francesco
authors.initials: GF
authors.lastname: Castino
authors.affiliation: Adaptive Immunity Laboratory, Humanitas Clinical and Research Center, Rozzano (Milano), Italy.
authors.forename: Debora
authors.initials: D
authors.lastname: Vignali
authors.affiliation: Laboratory of Cellular Immunology, Humanitas Clinical and Research Center, Rozzano (Milano), Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Erreni
authors.affiliation: Laboratory of Cellular Immunology, Humanitas Clinical and Research Center, Rozzano (Milano), Italy.|Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Marchesi
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy.
authors.forename: Cristiano
authors.initials: C
authors.lastname: Rumio
authors.affiliation: Adaptive Immunity Laboratory, Humanitas Clinical and Research Center, Rozzano (Milano), Italy.|Humanitas University, Rozzano (Milano), Italy.
authors.forename: Marinos
authors.initials: M
authors.lastname: Kallikourdis
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D057809:HEK293 Cells; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy; D019707:Receptors, Chemokine / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D019707:Receptors, Chemokine
keywords: Adoptive Cell Therapy; T cells; chemokines; fibrosis; tumor