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Research Articles

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

Camille-Charlotte Balança, Clara-Maria Scarlata, Marie Michelas, Christel Devaud, Victor Sarradin, Camille Franchet, Carlos Martinez Gomez, Carlos Gomez-Roca, Marie Tosolini, Diana Heaugwane, Françoise Lauzéral-Vizcaino, Lucile Mir-Mesnier, Virginie Féliu, Carine Valle, Frédéric Pont, Gwénaël Ferron, Laurence Gladieff, Stéphanie Motton, Yann Tanguy Le Gac, Agnès Dupret-Bories, Jérôme Sarini, Benjamin Vairel, Claire Illac, Aurore Siegfried-Vergnon, Eliane Mery, Jean-Jacques Fournié, Sébastien Vergez, Jean-Pierre Delord, Philippe Rochaix, Alejandra Martinez and Maha Ayyoub
Camille-Charlotte Balança
1Cancer Research Center of Toulouse, INSERM UMR 1037, Toulouse, France.
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Clara-Maria Scarlata
1Cancer Research Center of Toulouse, INSERM UMR 1037, Toulouse, France.
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  • ORCID record for Clara-Maria Scarlata
Marie Michelas
1Cancer Research Center of Toulouse, INSERM UMR 1037, Toulouse, France.
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Christel Devaud
1Cancer Research Center of Toulouse, INSERM UMR 1037, Toulouse, France.
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Victor Sarradin
1Cancer Research Center of Toulouse, INSERM UMR 1037, Toulouse, France.
2Department of Medical Oncology, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse, Toulouse, France.
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Camille Franchet
3Department of Pathology, Centre Hospitalier Universitaire, Institut Universitaire du Cancer de Toulouse, Toulouse, France.
4Université Toulouse III Paul Sabatier, Toulouse, France.
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Carlos Martinez Gomez
1Cancer Research Center of Toulouse, INSERM UMR 1037, Toulouse, France.
5Department of Surgery, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse, Toulouse, France.
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Carlos Gomez-Roca
1Cancer Research Center of Toulouse, INSERM UMR 1037, Toulouse, France.
2Department of Medical Oncology, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse, Toulouse, France.
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Marie Tosolini
6Technological Pole and Bioinformatic Platform, Cancer Research Center of Toulouse, INSERM UMR 1037, Toulouse, France.
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  • ORCID record for Marie Tosolini
Diana Heaugwane
7Department of Pathology, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse, Toulouse, France.
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Françoise Lauzéral-Vizcaino
1Cancer Research Center of Toulouse, INSERM UMR 1037, Toulouse, France.
4Université Toulouse III Paul Sabatier, Toulouse, France.
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Lucile Mir-Mesnier
8Immune Monitoring Core Facility, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse, Toulouse, France.
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Virginie Féliu
1Cancer Research Center of Toulouse, INSERM UMR 1037, Toulouse, France.
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Carine Valle
6Technological Pole and Bioinformatic Platform, Cancer Research Center of Toulouse, INSERM UMR 1037, Toulouse, France.
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Frédéric Pont
6Technological Pole and Bioinformatic Platform, Cancer Research Center of Toulouse, INSERM UMR 1037, Toulouse, France.
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Gwénaël Ferron
5Department of Surgery, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse, Toulouse, France.
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Laurence Gladieff
2Department of Medical Oncology, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse, Toulouse, France.
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Stéphanie Motton
9Department of Surgery, Centre Hospitalier Universitaire, Institut Universitaire du Cancer de Toulouse, Toulouse, France.
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Yann Tanguy Le Gac
9Department of Surgery, Centre Hospitalier Universitaire, Institut Universitaire du Cancer de Toulouse, Toulouse, France.
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Agnès Dupret-Bories
5Department of Surgery, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse, Toulouse, France.
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Jérôme Sarini
5Department of Surgery, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse, Toulouse, France.
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Benjamin Vairel
9Department of Surgery, Centre Hospitalier Universitaire, Institut Universitaire du Cancer de Toulouse, Toulouse, France.
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Claire Illac
7Department of Pathology, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse, Toulouse, France.
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Aurore Siegfried-Vergnon
3Department of Pathology, Centre Hospitalier Universitaire, Institut Universitaire du Cancer de Toulouse, Toulouse, France.
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Eliane Mery
7Department of Pathology, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse, Toulouse, France.
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Jean-Jacques Fournié
1Cancer Research Center of Toulouse, INSERM UMR 1037, Toulouse, France.
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Sébastien Vergez
4Université Toulouse III Paul Sabatier, Toulouse, France.
9Department of Surgery, Centre Hospitalier Universitaire, Institut Universitaire du Cancer de Toulouse, Toulouse, France.
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Jean-Pierre Delord
1Cancer Research Center of Toulouse, INSERM UMR 1037, Toulouse, France.
2Department of Medical Oncology, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse, Toulouse, France.
4Université Toulouse III Paul Sabatier, Toulouse, France.
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Philippe Rochaix
7Department of Pathology, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse, Toulouse, France.
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Alejandra Martinez
1Cancer Research Center of Toulouse, INSERM UMR 1037, Toulouse, France.
5Department of Surgery, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse, Toulouse, France.
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Maha Ayyoub
1Cancer Research Center of Toulouse, INSERM UMR 1037, Toulouse, France.
4Université Toulouse III Paul Sabatier, Toulouse, France.
8Immune Monitoring Core Facility, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse, Toulouse, France.
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  • For correspondence: maha.ayyoub@inserm.fr
DOI: 10.1158/2326-6066.CIR-19-0855 Published July 2020
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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.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).

  • Cancer Immunol Res 2020;8:869–82

  • Received October 29, 2019.
  • Revision received February 4, 2020.
  • Accepted April 9, 2020.
  • Published first April 15, 2020.
  • ©2020 American Association for Cancer Research.
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Cancer Immunology Research: 8 (7)
July 2020
Volume 8, Issue 7
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Dual Relief of T-lymphocyte Proliferation and Effector Function Underlies Response to PD-1 Blockade in Epithelial Malignancies
Camille-Charlotte Balança, Clara-Maria Scarlata, Marie Michelas, Christel Devaud, Victor Sarradin, Camille Franchet, Carlos Martinez Gomez, Carlos Gomez-Roca, Marie Tosolini, Diana Heaugwane, Françoise Lauzéral-Vizcaino, Lucile Mir-Mesnier, Virginie Féliu, Carine Valle, Frédéric Pont, Gwénaël Ferron, Laurence Gladieff, Stéphanie Motton, Yann Tanguy Le Gac, Agnès Dupret-Bories, Jérôme Sarini, Benjamin Vairel, Claire Illac, Aurore Siegfried-Vergnon, Eliane Mery, Jean-Jacques Fournié, Sébastien Vergez, Jean-Pierre Delord, Philippe Rochaix, Alejandra Martinez and Maha Ayyoub
Cancer Immunol Res July 1 2020 (8) (7) 869-882; DOI: 10.1158/2326-6066.CIR-19-0855

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Dual Relief of T-lymphocyte Proliferation and Effector Function Underlies Response to PD-1 Blockade in Epithelial Malignancies
Camille-Charlotte Balança, Clara-Maria Scarlata, Marie Michelas, Christel Devaud, Victor Sarradin, Camille Franchet, Carlos Martinez Gomez, Carlos Gomez-Roca, Marie Tosolini, Diana Heaugwane, Françoise Lauzéral-Vizcaino, Lucile Mir-Mesnier, Virginie Féliu, Carine Valle, Frédéric Pont, Gwénaël Ferron, Laurence Gladieff, Stéphanie Motton, Yann Tanguy Le Gac, Agnès Dupret-Bories, Jérôme Sarini, Benjamin Vairel, Claire Illac, Aurore Siegfried-Vergnon, Eliane Mery, Jean-Jacques Fournié, Sébastien Vergez, Jean-Pierre Delord, Philippe Rochaix, Alejandra Martinez and Maha Ayyoub
Cancer Immunol Res July 1 2020 (8) (7) 869-882; DOI: 10.1158/2326-6066.CIR-19-0855
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