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Transfer of in vitro-expanded naive T cells after lymphodepletion enhances antitumor immunity through the induction of polyclonal antitumor effector T cells.

ABSTRACT: The adoptive transfer of effector T cells combined with lymphodepletion has demonstrated promising antitumor effects in mice and humans, although the availability of tumor-specific T cells is limited. We and others have also demonstrated that the transfer of polyclonal naïve T cells induces tumor-specific effector T cells and enhances antitumor immunity after lymphodepletion. Because tumors have been demonstrated to induce immunosuppressive networks and regulate the function of T cells, obtaining a sufficient number of fully functional naïve T cells that are able to differentiate into tumor-specific effector T cells remains difficult. To establish culture methods to obtain a large number of polyclonal T cells that are capable of differentiating into tumor-specific effector T cells, naïve T cells were activated with anti-CD3 mAbs in vitro. These cells were stimulated with IL-2 and IL-7 for the CD8 subset or with IL-7 and IL-23 for the CD4 subset. Transfer of these hyperexpanded T cells after lymphodepletion showed significant antitumor efficacy, and tumor-specific effector T cells were primed from these expanded T cells in tumor-bearing hosts. Moreover, these ex vivo-expanded T cells maintained T cell receptor diversity and showed long-term persistence of memory against specific tumors. Further analyses revealed that combination therapy consisting of vaccination with dendritic cells that were co-cultured with irradiated whole tumor cells and the transfer of ex vivo-expanded T cells significantly enhanced antitumor immunity. These results indicate that the transfer of ex vivo-expanded polyclonal T cells can be combined with other immunotherapies and augment antitumor effects.

SUBMITTER: Tanaka T

PROVIDER: S-EPMC5576657 | biostudies-other | 2017

REPOSITORIES: biostudies-other

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Transfer of in vitro-expanded naïve T cells after lymphodepletion enhances antitumor immunity through the induction of polyclonal antitumor effector T cells.

Tanaka Tomohiro T Watanabe Satoshi S Takahashi Miho M Sato Ko K Saida Yu Y Baba Junko J Arita Masashi M Sato Miyuki M Ohtsubo Aya A Shoji Satoshi S Nozaki Koichiro K Ichikawa Kosuke K Kondo Rie R Aoki Nobumasa N Ohshima Yasuyoshi Y Sakagami Takuro T Abe Tetsuya T Moro Hiroshi H Koya Toshiyuki T Tanaka Junta J Kagamu Hiroshi H Yoshizawa Hirohisa H Kikuchi Toshiaki T

PloS one 20170830 8

The adoptive transfer of effector T cells combined with lymphodepletion has demonstrated promising antitumor effects in mice and humans, although the availability of tumor-specific T cells is limited. We and others have also demonstrated that the transfer of polyclonal naïve T cells induces tumor-specific effector T cells and enhances antitumor immunity after lymphodepletion. Because tumors have been demonstrated to induce immunosuppressive networks and regulate the function of T cells, obtainin ...[more]

PMID: 28854279

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Project description:Cancer immunotherapy using monoclonal antibodies (mAbs) to immune checkpoint (e.g., PD-1) has revolutionized the cancer treatments with long-term clinical benefits and being applicable to a wide range of tumors. However, a significant fraction of cancer patients does not respond to PD-1 blockade-based monotherapy. Considering the potential of combinatorial therapies in overcoming existing limitations of cancer immunotherapy, there is an increasing need to identify small-molecule modulators of immune cells capable of augmenting the effect of PD-1 blockade, leading to better cancer treatment. Although epigenetic drugs have shown potential in combination therapy, the lack of sequence specificity is a major concern. Pyrrole–imidazole polyamide (PIP), a selective DNA-binding small molecule, can guide epigenetic modulators to enable targeted gene activation. Here, we prepared and screened a library of PIPs encompassing the distinct PIPs conjugated with P300/CBP-selective bromodomain inhibitor (BI), which acts as a P300/CBP recruiter, and identified a PIP called BI-PIP-R that can trigger the targeted induction of the peroxisome proliferator-activated receptor-gamma coactivator 1 alpha/beta (PGC-1a/b), a regulator of mitochondrial activation and biogenesis. We further improved the chemical architecture of BI-PIP-R using a tri-arginine vector for better nuclear accumulation. This designer dual-functional molecule termed EnPGC-1 that enhanced mitochondrial activation, energy metabolism, proliferation of CD8+ T cells in vitro, and, in particular, enhanced oxidative phosphorylation (OXPHOS), a feature of long-lived memory T cells. Genome-wide gene analysis also suggested that EnPGC-1 and not the control compounds can regulate of T cell activation as a major biological process. EnPGC-1 also synergized with PD-1 blockade to enhance antitumor immunity and improved the survival. Together, this study represents the first example of a programmable DNA-based epigenetic drug with the potential to overcome the existing issues in cancer immunotherapy.

Project description:Cancer immunotherapy using monoclonal antibodies (mAbs) to immune checkpoint (e.g., PD-1) has revolutionized the cancer treatments with long-term clinical benefits and being applicable to a wide range of tumors. However, a significant fraction of cancer patients does not respond to PD-1 blockade-based monotherapy. Considering the potential of combinatorial therapies in overcoming existing limitations of cancer immunotherapy, there is an increasing need to identify small-molecule modulators of immune cells capable of augmenting the effect of PD-1 blockade, leading to better cancer treatment. Although epigenetic drugs have shown potential in combination therapy, the lack of sequence specificity is a major concern. Pyrrole–imidazole polyamide (PIP), a selective DNA-binding small molecule, can guide epigenetic modulators to enable targeted gene activation. Here, we prepared and screened a library of PIPs encompassing the distinct PIPs conjugated with P300/CBP-selective bromodomain inhibitor (BI), which acts as a P300/CBP recruiter, and identified a PIP called BI-PIP-R that can trigger the targeted induction of the peroxisome proliferator-activated receptor-gamma coactivator 1 alpha/beta (PGC-1a/b), a regulator of mitochondrial activation and biogenesis. We further improved the chemical architecture of BI-PIP-R using a tri-arginine vector for better nuclear accumulation. This designer dual-functional molecule termed EnPGC-1 that enhanced mitochondrial activation, energy metabolism, proliferation of CD8+ T cells in vitro, and, in particular, enhanced oxidative phosphorylation (OXPHOS), a feature of long-lived memory T cells. Genome-wide gene analysis also suggested that EnPGC-1 and not the control compounds can regulate T cell activation as a major biological process. EnPGC-1 also synergizes with PD-1 blockade that enhances antitumor immunity and improves the survival. Together, this study represents the first example of a programmable DNA-based epigenetic drug with the potential to overcome the existing issues in cancer immunotherapy.

Dataset Information

Transfer of in vitro-expanded naive T cells after lymphodepletion enhances antitumor immunity through the induction of polyclonal antitumor effector T cells.

Publications

Transfer of in vitro-expanded naïve T cells after lymphodepletion enhances antitumor immunity through the induction of polyclonal antitumor effector T cells.

Similar Datasets

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