Two-photon imaging of intratumoral CD8+ T cell cytotoxic activity during adoptive T cell therapy in mice

Breart, Béatrice; Lemaı̂tre, Fabrice; Celli, Susanna; Bousso, Philippe

doi:10.1172/jci34388

Cited by 262 publications

(287 citation statements)

References 32 publications

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“…Previous intravital imaging studies indicated that long-lasting CTL:tumor cell interactions support tumor cell killing (36) and tumor immunotherapy models show that CTLs initiate relevant tumor regression few days after adoptive transfer. Besides initial activation, CTL are required to maintain a sustained effector phenotype within the tumor microenvironment (37) for prolonged time periods to efficiently eradicate tumors.…”

Section: Discussionmentioning

confidence: 99%

Focusing and sustaining the antitumor CTL effector killer response by agonist anti-CD137 mAb

Weigelin

Bolaños

Teijeira

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Cancer immunotherapy is undergoing significant progress due to recent clinical successes by refined adoptive T-cell transfer and immunostimulatory monoclonal Ab (mAbs). B16F10-derived OVA-expressing mouse melanomas resist curative immunotherapy with either adoptive transfer of activated anti-OVA OT1 CTLs or agonist anti-CD137 (4-1BB) mAb. However, when acting in synergistic combination, these treatments consistently achieve tumor eradication. Tumor-infiltrating lymphocytes that accomplish tumor rejection exhibit enhanced effector functions in both transferred OT-1 and endogenous cytotoxic T lymphocytes (CTLs). This is consistent with higher levels of expression of eomesodermin in transferred and endogenous CTLs and with intravital live-cell two-photon microscopy evidence for more efficacious CTL-mediated tumor cell killing. Anti-CD137 mAb treatment resulted in prolonged intratumor persistence of the OT1 CTL-effector cells and improved function with focused and confined interaction kinetics of OT-1 CTL with target cells and increased apoptosis induction lasting up to six days postadoptive transfer. The synergy of adoptive T-cell therapy and agonist anti-CD137 mAb thus results from in vivo enhancement and sustainment of effector functions.

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Section: Discussionmentioning

confidence: 99%

Focusing and sustaining the antitumor CTL effector killer response by agonist anti-CD137 mAb

Weigelin

Bolaños

Teijeira

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Many clinical trials have now been conducted using genetically engineered T cells specific for tumor antigens as well as TILs, and some objective responses have been achieved (4,5). It is clear from mouse models that adoptively transferred antigen-specific T cells are capable of eradicating established cancer (6)(7)(8), and the ability of CTLs to directly kill tumor and/or stromal cells is thought to be important for tumor elimination (9)(10)(11). Nonetheless, cytokines such as IFNg and TNFa produced by T cells are also likely to contribute to the prevention of tumor growth by ACT via mechanisms other than cell lysis (12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

Cytotoxic T Lymphocytes Block Tumor Growth Both by Lytic Activity and IFNγ-Dependent Cell-Cycle Arrest

Matsushita

Hosoi

Ueha

et al. 2015

Cancer Immunology Research

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To understand global effector mechanisms of CTL therapy, we performed microarray gene expression analysis in a murine model using pmel-1 T-cell receptor (TCR) transgenic T cells as effectors and B16 melanoma cells as targets. In addition to upregulation of genes related to antigen presentation and the MHC class I pathway, and cytotoxic effector molecules, cell-cycle-promoting genes were downregulated in the tumor on days 3 and 5 after CTL transfer. To investigate the impact of CTL therapy on the cell cycle of tumor cells in situ, we generated B16 cells expressing a fluorescent ubiquitination-based cell-cycle indicator (B16-fucci) and performed CTL therapy in mice bearing B16-fucci tumors. Three days after CTL transfer, we observed diffuse infiltration of CTLs into the tumor with a large number of tumor cells arrested at the G 1 phase of the cell cycle, and the presence of spotty apoptotic or necrotic areas. Thus, tumor growth suppression was largely dependent on G 1 cell-cycle arrest rather than killing by CTLs. Neutralizing antibody to IFNg prevented both tumor growth inhibition and G 1 arrest. The mechanism of G 1 arrest involved the downregulation of S-phase kinase-associated protein 2 (Skp2) and the accumulation of its target cyclin-dependent kinase inhibitor p27 in the B16-fucci tumor cells. Because tumor-infiltrating CTLs are far fewer in number than the tumor cells, we propose that CTLs predominantly regulate tumor growth via IFNg-mediated profound cytostatic effects rather than via cytotoxicity. This dominance of G 1 arrest over other mechanisms may be widespread but not universal because IFNg sensitivity varied among tumors.

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“…An early study measuring the lysis of peptide-pulsed B cells in lymph nodes using two-photon microscopy demonstrated target cell killing by CD8 + T cells in less than 20 min (5). In contrast, it was estimated that 6 h of cognate CD8 + T-cell contact were required to induce apoptosis of tumor cells in vivo (6). In studies with vaccinia virus, Leishmania, Listeria, and Toxoplasma, cognate T cells were seen changing their migratory behavior in the presence of microbial antigen, although pathogen killing was not observed (7)(8)(9)(10)(11).…”

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confidence: 99%

In vivo imaging of CD8⁺T cell-mediated elimination of malaria liver stages

Cockburn

Amino

Kelemen³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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285

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CD8 + T cells are specialized cells of the adaptive immune system capable of finding and eliminating pathogen-infected cells. To date it has not been possible to observe the destruction of any pathogen by CD8 + T cells in vivo. Here we demonstrate a technique for imaging the killing of liver-stage malaria parasites by CD8 + T cells bearing a transgenic T cell receptor specific for a parasite epitope. We report several features that have not been described by in vitro analysis of the process, chiefly the formation of large clusters of effector CD8 + T cells around infected hepatocytes. The formation of clusters requires antigen-specific CD8 + T cells and signaling by G protein-coupled receptors, although CD8 + T cells of unrelated specificity are also recruited to clusters. By combining mathematical modeling and data analysis, we suggest that formation of clusters is mainly driven by enhanced recruitment of T cells into larger clusters. We further show various death phenotypes of the parasite, which typically follow prolonged interactions between infected hepatocytes and CD8 + T cells. These findings stress the need for intravital imaging for dissecting the fine mechanisms of pathogen recognition and killing by CD8 + T cells.Plasmodium | immunity | lymphocytes

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Two-photon imaging of intratumoral CD8+ T cell cytotoxic activity during adoptive T cell therapy in mice

Cited by 262 publications

References 32 publications

Focusing and sustaining the antitumor CTL effector killer response by agonist anti-CD137 mAb

Focusing and sustaining the antitumor CTL effector killer response by agonist anti-CD137 mAb

Cytotoxic T Lymphocytes Block Tumor Growth Both by Lytic Activity and IFNγ-Dependent Cell-Cycle Arrest

In vivo imaging of CD8⁺T cell-mediated elimination of malaria liver stages

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Two-photon imaging of intratumoral CD8+ T cell cytotoxic activity during adoptive T cell therapy in mice

Cited by 262 publications

References 32 publications

Focusing and sustaining the antitumor CTL effector killer response by agonist anti-CD137 mAb

Focusing and sustaining the antitumor CTL effector killer response by agonist anti-CD137 mAb

Cytotoxic T Lymphocytes Block Tumor Growth Both by Lytic Activity and IFNγ-Dependent Cell-Cycle Arrest

In vivo imaging of CD8+T cell-mediated elimination of malaria liver stages

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In vivo imaging of CD8⁺T cell-mediated elimination of malaria liver stages