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Dual Relief of T-lymphocyte Proliferation and Effector Function Underlies Response to PD-1 Blockade in Epithelial Malignancies

Balança, Camille-Charlotte and Scarlata, Clara-Maria and Michelas, Marie and Devaud, Christel and Sarradin, Victor and Franchet, Camille and Martinez Gomez, Carlos and Gomez-Roca, Carlos and Tosolini, Marie and Heaugwane, Diana and Lauzéral-Vizcaino, Françoise and Mir-Mesnier, Lucile and Féliu, Virginie and Valle, Carine and Pont, Frédéric and Ferron, Gwénaël and Gladieff, Laurence and Motton, Stéphanie and Tanguy Le Gac, Yann and Dupret Bories, Agnès and Sarini, Jérôme and Vairel, Benjamin and Illac, Claire and Siegfried-Vergnon, Aurore and Mery, Eliane and Fournié, Jean-Jacques and Vergez, Sébastien and Delord, Jean-Pierre and Rochaix, Philippe and Martinez, Alejandra and Ayyoub, Maha Dual Relief of T-lymphocyte Proliferation and Effector Function Underlies Response to PD-1 Blockade in Epithelial Malignancies. (2020) Cancer Immunology Research, 8 (7). 869-882. ISSN 2326-6066

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Official URL: https://doi.org/10.1158/2326-6066.CIR-19-0855

Abstract

Although understanding of T-cell exhaustion is widely based on mouse models, its analysis in patients with cancer could provide clues indicating tumor sensitivity to immune checkpoint blockade (ICB). Data suggest a role for costimulatory pathways, particularly CD28, in exhausted T-cell responsiveness to PD-1/PD-L1 blockade. Here, we used single-cell transcriptomic, phenotypic, and functional approaches to dissect the relation between CD8+ T-cell exhaustion, CD28 costimulation, and tumor specificity in head and neck, cervical, and ovarian cancers. We found that memory tumor–specific CD8+ T cells, but not bystander cells, sequentially express immune checkpoints once they infiltrate tumors, leading, in situ, to a functionally exhausted population. Exhausted T cells were nonetheless endowed with effector and tumor residency potential but exhibited loss of the costimulatory receptor CD28 in comparison with their circulating memory counterparts. Accordingly, PD-1 inhibition improved proliferation of circulating tumor–specific CD8+ T cells and reversed functional exhaustion of specific T cells at tumor sites. In agreement with their tumor specificity, high infiltration of tumors by exhausted cells was predictive of response to therapy and survival in ICB-treated patients with head and neck cancer. Our results showed that PD-1 blockade–mediated proliferation/reinvigoration of circulating memory T cells and local reversion of exhaustion occur concurrently to control tumors.

Item Type:Article
HAL Id:hal-03203330
Audience (journal):International peer-reviewed journal
Uncontrolled Keywords:
Institution:French research institutions > Centre National de la Recherche Scientifique - CNRS (FRANCE)
French research institutions > Institut National de la Santé et de la Recherche Médicale - INSERM (FRANCE)
Université de Toulouse > Université Toulouse III - Paul Sabatier - UT3 (FRANCE)
Other partners > Institut Claudius Regaud - ICR (FRANCE)
Other partners > Centre Hospitalier Universitaire de Toulouse - CHU Toulouse (FRANCE)
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Deposited On:20 Apr 2021 15:15

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