PD-1 blockade restores helper activity of tumor-infiltrating, exhausted PD-1hiCD39+ CD4 T cells
Camille-Charlotte Balança
(1)
,
Anna Salvioni
(1)
,
Clara-Maria Scarlata
(1)
,
Marie Michelas
(1)
,
Carlos Martinez-Gomez
(1)
,
Carlos Gomez-Roca
(1, 2, 3, 4)
,
Victor Sarradin
(1, 2, 3)
,
Marie Tosolini
(1)
,
Carine Valle
(1)
,
Frédéric Pont
(1)
,
Gwénaël Ferron
(4)
,
Laurence Gladieff
(3)
,
Sébastien Vergez
(3, 4)
,
Agnès Dupret-Bories
(4)
,
Eliane Mery
(3, 2)
,
Philippe Rochaix
(3, 2)
,
Jean-Jacques Fournié
(1)
,
Jean-Pierre Delord
(1, 3, 2, 5)
,
Christel Devaud
(1)
,
Alejandra Martinez
(1, 4)
,
Maha Ayyoub
(1, 5)
Camille-Charlotte Balança
- Fonction : Auteur
- PersonId : 1216812
- ORCID : 0000-0002-3145-6022
Clara-Maria Scarlata
- Fonction : Auteur
- PersonId : 797975
- ORCID : 0000-0003-3429-2825
Carlos Martinez-Gomez
- Fonction : Auteur
- PersonId : 1224002
- ORCID : 0000-0002-9652-7880
Victor Sarradin
- Fonction : Auteur
- PersonId : 806705
- ORCID : 0000-0003-1675-7983
Marie Tosolini
- Fonction : Auteur
- PersonId : 768352
- ORCID : 0000-0001-5278-5952
- IdRef : 146550811
Frédéric Pont
- Fonction : Auteur
- PersonId : 756570
- ORCID : 0000-0002-5493-527X
- IdRef : 224672517
Gwénaël Ferron
- Fonction : Auteur
- PersonId : 802487
- ORCID : 0000-0002-8545-4700
Agnès Dupret-Bories
- Fonction : Auteur
- PersonId : 1246074
- IdHAL : agnes-dupret-bories
- ORCID : 0000-0002-7068-3500
- IdRef : 147322693
Eliane Mery
- Fonction : Auteur
- PersonId : 763697
- ORCID : 0000-0002-0354-4519
Philippe Rochaix
- Fonction : Auteur
- PersonId : 757016
- ORCID : 0000-0001-6238-1599
- IdRef : 05870759X
Jean-Jacques Fournié
- Fonction : Auteur
- PersonId : 178841
- IdHAL : jean-jacques-fournie
- ORCID : 0000-0001-6542-6908
- IdRef : 031095887
Christel Devaud
- Fonction : Auteur
- PersonId : 769564
- ORCID : 0000-0003-3511-3219
Alejandra Martinez
- Fonction : Auteur
- PersonId : 759037
- ORCID : 0000-0002-7633-3536
Maha Ayyoub
- Fonction : Auteur
- PersonId : 773870
- ORCID : 0000-0003-2022-0898
Résumé
Tumor antigen-specific CD4 T cells accumulate at tumor sites, evoking their involvement in antitumor effector functions in situ. Contrary to CD8 cytotoxic T lymphocyte exhaustion, that of CD4 T cells remains poorly appreciated. Here, using phenotypic, transcriptomic, and functional approaches, we characterized CD4 T cell exhaustion in patients with head and neck, cervical, and ovarian cancer. We identified a CD4 tumor-infiltrating lymphocyte (TIL) population, defined by high PD-1 and CD39 expression, which contained high proportions of cytokine-producing cells, although the quantity of cytokines produced by these cells was low, evoking an exhausted state. Terminal exhaustion of CD4 TILs was instated regardless of TIM-3 expression, suggesting divergence with CD8 T cell exhaustion. scRNA-Seq and further phenotypic analyses uncovered similarities with the CD8 T cell exhaustion program. In particular, PD-1hiCD39+ CD4 TILs expressed the exhaustion transcription factor TOX and the chemokine CXCL13 and were tumor antigen specific. In vitro, PD-1 blockade enhanced CD4 TIL activation, as evidenced by increased CD154 expression and cytokine secretion, leading to improved dendritic cell maturation and consequently higher tumor-specific CD8 T cell proliferation. Our data identify exhausted CD4 TILs as players in responsiveness to immune checkpoint blockade.
Domaines
Sciences du Vivant [q-bio]Format du dépôt | Notice |
---|---|
Type de dépôt | Article dans une revue |
Titre |
en
PD-1 blockade restores helper activity of tumor-infiltrating, exhausted PD-1hiCD39+ CD4 T cells
|
Résumé |
en
Tumor antigen-specific CD4 T cells accumulate at tumor sites, evoking their involvement in antitumor effector functions in situ. Contrary to CD8 cytotoxic T lymphocyte exhaustion, that of CD4 T cells remains poorly appreciated. Here, using phenotypic, transcriptomic, and functional approaches, we characterized CD4 T cell exhaustion in patients with head and neck, cervical, and ovarian cancer. We identified a CD4 tumor-infiltrating lymphocyte (TIL) population, defined by high PD-1 and CD39 expression, which contained high proportions of cytokine-producing cells, although the quantity of cytokines produced by these cells was low, evoking an exhausted state. Terminal exhaustion of CD4 TILs was instated regardless of TIM-3 expression, suggesting divergence with CD8 T cell exhaustion. scRNA-Seq and further phenotypic analyses uncovered similarities with the CD8 T cell exhaustion program. In particular, PD-1hiCD39+ CD4 TILs expressed the exhaustion transcription factor TOX and the chemokine CXCL13 and were tumor antigen specific. In vitro, PD-1 blockade enhanced CD4 TIL activation, as evidenced by increased CD154 expression and cytokine secretion, leading to improved dendritic cell maturation and consequently higher tumor-specific CD8 T cell proliferation. Our data identify exhausted CD4 TILs as players in responsiveness to immune checkpoint blockade.
|
Auteur(s) |
Camille-Charlotte Balança
1
, Anna Salvioni
1
, Clara-Maria Scarlata
1
, Marie Michelas
1
, Carlos Martinez-Gomez
1
, Carlos Gomez-Roca
1, 2, 3, 4
, Victor Sarradin
1, 2, 3
, Marie Tosolini
1
, Carine Valle
1
, Frédéric Pont
1
, Gwénaël Ferron
4
, Laurence Gladieff
3
, Sébastien Vergez
3, 4
, Agnès Dupret-Bories
4
, Eliane Mery
3, 2
, Philippe Rochaix
3, 2
, Jean-Jacques Fournié
1
, Jean-Pierre Delord
1, 3, 2, 5
, Christel Devaud
1
, Alejandra Martinez
1, 4
, Maha Ayyoub
1, 5
1
CRCT -
Centre de Recherches en Cancérologie de Toulouse
( 511697 )
- Centre de Recherches en Cancérologie de Toulouse
2 Avenue Hubert Curien
31037 Toulouse Cedex 1
FRANCE
- France
2
Institut Claudius Regaud
( 300150 )
- France
3
IUCT Oncopole - UMR 1037 -
Institut Universitaire du Cancer de Toulouse - Oncopole
( 450027 )
- Av. Irène Joliot-Curie 31100 Toulouse
- France
4
CHU Toulouse -
Centre Hospitalier Universitaire de Toulouse
( 300075 )
- regroupe les hôpitaux Purpan, Rangueil, Pierre-Paul Riquet, Larey, Paule de Viguier, Hôtel Dieu Saint-Jacques, La Grave, etc.
- France
5
UT3 -
Université Toulouse III - Paul Sabatier
( 217752 )
- 118 route de Narbonne - 31062 Toulouse
- France
|
Langue du document |
Anglais
|
Nom de la revue |
|
Vulgarisation |
Non
|
Comité de lecture |
Oui
|
Audience |
Internationale
|
Date de publication |
2021-01-25
|
Volume |
6
|
Numéro |
2
|
Domaine(s) |
|
Mots-clés |
en
Cancer immunotherapy, Immunology, T cells
|
DOI | 10.1172/jci.insight.142513 |
PubMed Central | PMC7934837 |
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