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Supplementary Figure S7 from T Cells Redirected to a Minor Histocompatibility Antigen Instruct Intratumoral TNFα Expression and Empower Adoptive Cell Therapy for Solid Tumors

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posted on 2023-03-31, 01:06 authored by Teresa Manzo, Tabea Sturmheit, Veronica Basso, Elisabetta Petrozziello, Rodrigo Hess Michelini, Michela Riba, Massimo Freschi, Angela R. Elia, Matteo Grioni, Flavio Curnis, Maria Pia Protti, Ton N. Schumacher, Reno Debets, Melody A. Swartz, Angelo Corti, Matteo Bellone, Anna Mondino

Principal component and GSEA analyses of microarray data.

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European Community

AIRC

European Research Counci

Swiss Cancer League

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ARTICLE ABSTRACT

Donor-derived allogeneic T cells evoke potent graft versus tumor (GVT) effects likely due to the simultaneous recognition of tumor-specific and host-restricted minor histocompatibility (H) antigens. Here we investigated whether such effects could be reproduced in autologous settings by TCR gene–engineered lymphocytes. We report that T cells redirected either to a broadly expressed Y-encoded minor H antigen or to a tumor-associated antigen, although poorly effective if individually transferred, when simultaneously administered enabled acute autochthonous tumor debulking and resulted in durable clinical remission. Y-redirected T cells proved hyporesponsive in peripheral lymphoid organs, whereas they retained effector function at the tumor site, where in synergy with tumor-redirected lymphocytes, they instructed TNFα expression, endothelial cell activation, and intratumoral T-cell infiltration. While neutralizing TNFα hindered GVT effects by the combined T-cell infusion, a single injection of picogram amounts of NGR-TNF, a tumor vessel–targeted TNFα derivative currently in phase III clinical trials, substituted for Y-redirected cells and enabled tumor debulking by tumor-redirected lymphocytes. Together, our results provide new mechanistic insights into allogeneic GVT, validate the importance of targeting the tumor and its associated stroma, and prove the potency of a novel combined approach suitable for immediate clinical implementation. Cancer Res; 77(3); 658–71. ©2016 AACR.

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