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T cell–encoded CD80 and 4-1BBL induce auto- and transcostimulation, resulting in potent tumor rejection

Nature Medicine volume 13, pages 1440–1449 (2007)Cite this article

An Author Correction to this article was published on 28 February 2024

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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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Figure 1: Constitutive coexpression of CD80 and 4-1BBL in human T lymphocytes elicits robust proliferative responses after cyclic stimulations through their endogenous T cell receptor or through a chimeric antigen receptor.
Figure 2: Eradication of established PC3-PSMA tumors in SCID-Beige mice after treatment with Pz1+ T cells coexpressing CD80 and 4-1BBL.
Figure 3: Robust, tumor antigen–dependent, in vivo accumulation of CD80+4-1BBL+ T lymphocytes.
Figure 4: CD80 and 4-1BBL and their receptors, CD28 and 4-1BB, colocalize at the immunological synapse to costimulate T cells in cis.
Figure 5: CD80- and 4-1BBL–expressing T lymphocytes transcostimulate unmodified, antigen-specific bystander T cells through physical contact.
Figure 6: The accumulation of adoptively transferred, PSMA-redirected T lymphocytes at tumor sites is augmented by Pz1+CD80+4-1BBL+, but not 19z1+CD80+4-1BBL+, T cells.

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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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Authors and Affiliations

  1. Center for Cell Engineering, Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, 10021, New York, USA

    Matthias T Stephan, Renier J Brentjens, Alex H Chang & Michel Sadelain

  2. Immunology Graduate Program, Weill Graduate School of Medical Sciences, Cornell University, New York, 10021, New York, USA

    Matthias T Stephan & Michel Sadelain

  3. Department of Radiology, MSKCC, New York, 10021, New York, USA

    Vladimir Ponomarev & Konstantin V Dobrenkov

  4. Department of Medicine, MSKCC, New York, 10021, New York, USA

    Renier J Brentjens & Michel Sadelain

  5. Department of Epidemiology and Biostatistics, MSKCC, New York, 10021, New York, USA

    Glenn Heller

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Correspondence to Michel Sadelain.

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Supplementary Text and Figures

Supplementary Figs. 1–9 (PDF 2421 kb)

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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