Abstract
To reject tumors, T cells must overcome poor tumor immunogenicity and an adverse tumor microenvironment. Providing agonistic costimulatory signals to tumor-infiltrating T cells to augment T cell function remains a challenge for the implementation of safe and effective immunotherapy. We hypothesized that T cells overexpressing selected costimulatory ligands could serve as cellular vehicles mediating powerful, yet constrained, anatomically targeted costimulation. Here, we show that primary human T cells expressing CD80 and 4-1BB ligand (4-1BBL) vigorously respond to tumor cells lacking costimulatory ligands and provoke potent rejection of large, systemic tumors in immunodeficient mice. In addition to showing costimulation of bystander T cells (transcostimulation), we show the effect of CD80 and 4-1BBL binding to their respective receptors in the immunological synapse of isolated single cells (autocostimulation). This new strategy of endowing T cells with constitutively expressed costimulatory ligands could be extended to other ligand-receptor pairs and used to enhance any targeted adoptive transfer therapy.
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Change history
28 February 2024
A Correction to this paper has been published: https://doi.org/10.1038/s41591-024-02882-2
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Acknowledgements
We thank J. Koutcher and C. Le for magnetic resonance imaging scans provided by the MSKCC Small Animal Imaging Core Facility, supported in part by the National Institutes of Health (NIH) Small Animal Imaging Research Program Grant No. R24 CA83084 and the NIH Center Grant No. P30CA08748. We thank K. Manova for consulting and technical assistance for the confocal studies, J. Hendrikx for MoFlo cell sorts and K. LaPerle for the necropsies. Anti-idiotypic antibodies specific for Pz1 and 19z1 were kindly provided by I. Rivière (MSKCC). We thank R. O'Reilly (MSKCC) for Caco-2 tumor cells retrovirally transduced to express CMV pp65 and M. Olszewska (MSKCC) for the SFG-CBR-luc-eGFP fusion plasmid. We also thank S. Samakoglu (MSKCC) for the pSLII80-hU6 plasmid as well as for the shRNA for β-globin. This work was supported by NIH grant CA59350, W.H. Goodwin and A. Goodwin and the Commonwealth Cancer Foundation for Research, the Experimental Therapeutics Center of MSKCC, and Golfers against Cancer. M.T.S. is a recipient of the Cancer Research Institute predoctoral fellowship.
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Supplementary Movie
The 3D-overlay projection shows a two-cell cluster from our confocal studies (Fig. 4a). A human CD8+dsRed-4-1BBL+Pz1+ T cell labelled with FITC-CTB engages a PSMA+ LNCaP tumor cell (Red = dsRed-4-1BBL, Magenta = 4-1BB-Cy5, Green = FITC-CTB). The exact protocol is detailed in Methods.The rotating 3D-projection has been obtained by converting a confocal z-stack (20 μm at 1 μm) using Velocity software (Improvision). (MOV 572 kb)
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Stephan, M., Ponomarev, V., Brentjens, R. et al. T cell–encoded CD80 and 4-1BBL induce auto- and transcostimulation, resulting in potent tumor rejection. Nat Med 13, 1440–1449 (2007). https://doi.org/10.1038/nm1676
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DOI: https://doi.org/10.1038/nm1676
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