In vivo imaging of cytotoxic T cell infiltration and elimination of a solid tumor

Boissonnas, Alexandre; Fetler, Luc; Zeelenberg, Ingrid S.; Hugues, Stéphanie; Amigorena, Sébastian

doi:10.1084/jem.20061890

Cited by 342 publications

(296 citation statements)

References 33 publications

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“…Similarly to our findings with Plasmodium, nonspecific CD8 + T cells were recruited to tumors only in the presence of tumor-specific CD8 + T cells (21). However, in this model the recruited nonspecific cells had very distinct motility characteristics from the specific cells (22).…”

Section: Discussionsupporting

confidence: 52%

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.

125

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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Section: Discussionsupporting

confidence: 52%

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.

125

285

View full text Add to dashboard Cite

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“…The absence of priming functions by TIDC in brain gliomas strongly suggests that they are unable to reactivate glioma-infiltrating lymphocytes in situ, which could explain the reduction in T-cell numbers observed during the course of tumor development. Indeed, T-cell activation is critically important for the infiltration of T cells deep into the tumor tissue [40], and T cells which do not re-encounter their antigen disappear from the CNS, either via migration back to the periphery [41] or via apoptosis [42]. Interestingly, in glioblastoma patients, invading T cells have been reported to undergo apoptosis [43].…”

Section: Discussionmentioning

confidence: 99%

Site‐specific anti‐tumor immunity: Differences in DC function, TGF‐β production and numbers of intratumoral Foxp3⁺ Treg

et al. 2009

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Gliomas localized within the CNS are generally not rejected by the immune system despite being immunogenic. This failure of the immune system has been associated both with glioma-derived immunosuppressive molecules and the immune-privileged state of the CNS. However, the relative contribution of tumor location to the glioma-mediated immunosuppression, as well as the immune mechanisms involved in the failure of glioma rejection are not fully defined. We report here that syngeneic GL261 gliomas growing either intracranially or subcutaneously in mice are infiltrated by DC and T cells. However, only subcutaneous gliomas elicit an effective anti-tumor immune response. In contrast to DC infiltrating subcutaneously grown GL261 gliomas, tumor-infiltrating DC from intracranial gliomas do not activate antigen-dependent T-cell proliferation in vitro. In addition, brain-localized GL261 gliomas are characterized by significantly higher numbers of Foxp3 1 Treg and higher levels of TGF-b1 mRNA and protein expression when compared with GL261 gliomas in the skin. Our data show that gliomas in the CNS, but not in the skin, give rise to TGF-b production and accumulation of both Treg and functionally impaired DC. Thus, not the tumor itself, but its location dictates the efficiency of the antitumor immune response.Key words: DC . Immune privilege . Treg . Tumor immunity Supporting Information available online IntroductionMalignant gliomas, especially the most frequent and aggressive form known as glioblastoma multiforme, are among the most fatal types of tumors. The best standard of care for glioblastoma multiforme, consisting of surgery followed by radiotherapy and chemotherapy with temozolomide, is associated with a median overall survival of 14.6 months following diagnosis [1]. Gliomas have been shown to result in reduced peripheral T-cell responses [2], down-modulated function of circulating APC [3] and particularly to suppressed maturation of peripheral DC [4]. In addition, the localization of the glioma within the immune-privileged CNS, combined with the production of tumorderived immunosuppressive molecules including , , VEGF [9] and prostaglandins [10], is suggested to account for the absence of a successful anti-tumor immune Ã These authors contributed equally to this work. response. As a consequence, glioma patients fail to generate an effective immune response against the intracranially growing tumors. Although it occurs rarely, gliomas are able to metastasize to locations outside of the brain [11]. The low frequency of peripheral glioma metastases might be due to an efficient recognition of tumor cells outside of the CNS. Gliomas express tumor-associated antigens such as ER-2, gp100, and MAGE-1, which can be recognized by cytotoxic T lymphocyte clones [12]. Furthermore, T-cell clonal expansion has been detected in glioma patients [13] and vaccination of patients with autologous tumor lysate-pulsed DC or autologous tumor peptide-pulsed DC [14] can elicit tumor-specific T-cell responses and infiltration of cytotoxic and me...

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“…However, it is possible that low-doses of anti-angiogenic drugs, such as sunitinib, might further reduce immunoregulatory cell populations in support of an even more robust pro-inflammatory TME when combined with DLK1/DLK2-targeted vaccines. 48 When taken in the context to existing paradigms for temporal cascades of T cell infiltration into the TME, 49,50 we would propose that the vaccine-induced DLK1-and DLK2-specific T cells might represent an initial wave of effector TILs that trim and promote the maturation of tumor-associated blood vessels, leading to VN. The normalized TME is conducive to DC maturation and the subsequent cross-priming of "second set" CD8 C T cell responses reactive against TAA acquired by DC within the TME.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic efficacy of combined vaccination against tumor pericyte-associated antigens DLK1 and DLK2 in mice

et al. 2017

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When compared with vascular cells in normal tissues, pericytes and vascular endothelial cells (VEC) in tumor blood vessels exhibit altered morphology and epigenetic programming that leads to the expression of unique antigens that allow for differential recognition by CD8 C T cells. We have previously shown that the Notch antagonist delta-like homolog 1 (DLK1) is a tumor pericyte-associated antigen expressed in setting of melanoma and a range of carcinomas. In this report, we show that therapeutic vaccination against DLK1 in murine models results in slowed tumor growth, but also to the compensatory expression of the DLK1 homolog, DLK2, by tumor-associated pericytes. Vaccines targeting both DLK1 and DLK2 resulted in superior antitumor benefits in association with improved activation and recruitment of antigen-specific Type 1 CD8 C T cells, reduced presence of myeloid-derived suppressive cells, T regulatory cell and tumor vascular normalization. The antitumor efficacy of vaccines coordinately targeting DLK1 and DLK2 was further improved by inclusion of PD-L1 blockade, thus defining a combination immunotherapy theoretically suitable for the treatment of a broad range of solid (vascularized) cancers.

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In vivo imaging of cytotoxic T cell infiltration and elimination of a solid tumor

Cited by 342 publications

References 33 publications

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

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

Site‐specific anti‐tumor immunity: Differences in DC function, TGF‐β production and numbers of intratumoral Foxp3⁺ Treg

Therapeutic efficacy of combined vaccination against tumor pericyte-associated antigens DLK1 and DLK2 in mice

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In vivo imaging of cytotoxic T cell infiltration and elimination of a solid tumor

Cited by 342 publications

References 33 publications

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

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

Site‐specific anti‐tumor immunity: Differences in DC function, TGF‐β production and numbers of intratumoral Foxp3+ Treg

Therapeutic efficacy of combined vaccination against tumor pericyte-associated antigens DLK1 and DLK2 in mice

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

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

Site‐specific anti‐tumor immunity: Differences in DC function, TGF‐β production and numbers of intratumoral Foxp3⁺ Treg