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Antitumor T-cell Ho...
Antitumor T-cell Homeostatic Activation Is Uncoupled from Homeostatic Inhibition by Checkpoint Blockade
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- Marshall, Netonia (författare)
- Department of Medicine, Division of Hematology and Medical Oncology, Icahn School of Medicine, Mount Sinai Hospital, New York, USA
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- Hutchinson, Keino (författare)
- Department of Pharmacological Sciences, Icahn School of Medicine, Mount Sinai Hospital, New York, USA
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- Marron, Thomas U. (författare)
- Department of Medicine, Division of Hematology and Medical Oncology, Icahn School of Medicine, Mount Sinai Hospital, New York, USA
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- Aleynick, Mark (författare)
- Department of Medicine, Division of Hematology and Medical Oncology, Icahn School of Medicine, Mount Sinai Hospital, New York, USA
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- Hammerich, Linda (författare)
- Department of Medicine, Division of Hematology and Medical Oncology, Icahn School of Medicine, Mount Sinai Hospital, New York, USA
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- Upadhyay, Ranjan (författare)
- 1Department of Medicine, Division of Hematology and Medical Oncology, Icahn School of Medicine, Mount Sinai Hospital, New York, New York.
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- Svensson-Arvelund, Judit, 1982- (författare)
- Department of Medicine, Division of Hematology and Medical Oncology, Icahn School of Medicine, Mount Sinai Hospital, New York, USA
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- Brown, Brian D. (författare)
- Department of Genetics and Genomic Sciences, Icahn School of Medicine, Mount Sinai Hospital, New York, USA
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- Merad, Miriam (författare)
- Department of Medicine, Division of Hematology and Medical Oncology, Icahn School of Medicine, Mount Sinai Hospital, New York, New York.;4Department of Oncological Sciences, Icahn School of Medicine, Mount Sinai Hospital, New York, USA
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- Brody, Joshua D. (författare)
- 1Department of Medicine, Division of Hematology and Medical Oncology, Icahn School of Medicine, Mount Sinai Hospital, New York, New York.
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(creator_code:org_t)
- 2019-11-01
- 2019
- Engelska.
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Ingår i: Cancer Discovery. - : American Association For Cancer Research (AACR). - 2159-8274 .- 2159-8290. ; 9:11, s. 1520-1537
- Relaterad länk:
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https://cancerdiscov...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- T-cell transfer into lymphodepleted recipients induces homeostatic activation and potentiates antitumor efficacy. In contrast to canonical T-cell receptor–induced activation, homeostatic activation yields a distinct phenotype and memory state whose regulatory mechanisms are poorly understood. Here, we show in patients and murine models that, following transfer into lymphodepleted bone marrow transplant (BMT) recipients, CD8+ T cells undergo activation but also simultaneous homeostatic inhibition manifested by upregulation of immune-checkpoint molecules and functional suppression. T cells transferred into BMT recipients were protected from homeostatic inhibition by PD-1/CTLA4 dual checkpoint blockade (dCB). This combination of dCB and BMT— ”immunotransplant”—increased T-cell homeostatic activation and antitumor T-cell responses by an order of magnitude. Like homeostatic activation, homeostatic inhibition is IL7/IL15-dependent, revealing mechanistic coupling of these two processes. Marked similarity in ex vivo modulation of post-BMT T cells in mice and patients is promising for the clinical translation of immunotransplant (NCT03305445) and for addressing homeostatic inhibition in T-cell therapies. SIGNIFICANCE: For optimal anticancer effect, T-cell therapies including chimeric antigen receptor T-cell, tumor-infiltrating lymphocyte, and transgenic T-cell therapies require transfer into lymphodepleted recipients and homeostatic activation; however, concomitant homeostatic inhibition mitigates T-cell therapies’ efficacy. Checkpoint blockade uncouples homeostatic inhibition from activation, amplifying T-cell responses. Conversely, tumors nonresponsive to checkpoint blockade or BMT are treatable with immunotransplant. © 2019 American Association for Cancer Research.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
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- ref (ämneskategori)
- art (ämneskategori)
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