Keratinocyte-derived cytokine TSLP promotes growth and metastasis of melanoma by regulating the tumor-associated immune microenvironment
Wenjin Yao
(1)
,
Beatriz German
(1)
,
Dounia Chraa
(2)
,
Antoine Braud
(1, 3)
,
Cecile Hugel
(1)
,
Pierre Meyer
(1)
,
Guillaume Davidson
(1)
,
Patrick Laurette
(1)
,
Gabrielle Mengus
(1)
,
Eric Flatter
(1)
,
Pierre Marschall
(1)
,
Justine Segaud
(1)
,
Marine Guivarch
(1)
,
Pierre Hener
(1)
,
Marie-Christine Birling
(4)
,
Dan Lipsker
(3)
,
Irwin Davidson
(1)
,
Mei Li
(1)
Cecile Hugel
- Fonction : Auteur
- PersonId : 1173088
- ORCID : 0000-0002-5472-0906
Pierre Meyer
- Fonction : Auteur
- PersonId : 1173089
- ORCID : 0000-0001-9547-7976
Guillaume Davidson
- Fonction : Auteur
- PersonId : 798306
- ORCID : 0000-0001-9272-3924
Patrick Laurette
- Fonction : Auteur
- PersonId : 1173090
- ORCID : 0000-0002-8941-612X
Gabrielle Mengus
- Fonction : Auteur
- PersonId : 739609
- IdHAL : gabrielle-mengus
- ORCID : 0000-0002-2844-1778
- IdRef : 253123909
Justine Segaud
- Fonction : Auteur
- PersonId : 1173091
- ORCID : 0000-0003-4687-7046
Marine Guivarch
- Fonction : Auteur
- PersonId : 1173092
- ORCID : 0000-0002-7051-9911
Marie-Christine Birling
- Fonction : Auteur
- PersonId : 1173093
- ORCID : 0000-0002-3372-8108
Dan Lipsker
- Fonction : Auteur
- PersonId : 765615
- ORCID : 0000-0003-4675-0336
- IdRef : 063760371
Irwin Davidson
Connectez-vous pour contacter l'auteur
- Fonction : Auteur correspondant
- PersonId : 742111
- IdHAL : irwin-davidson
- ORCID : 0000-0001-5533-1171
- IdRef : 075977249
Connectez-vous pour contacter l'auteur
Mei Li
Connectez-vous pour contacter l'auteur
- Fonction : Auteur correspondant
- PersonId : 741761
- IdHAL : mei-li
- ORCID : 0000-0003-4225-6699
- IdRef : 190600489
Connectez-vous pour contacter l'auteur
Résumé
Malignant melanoma is a major public health issue displaying frequent resistance to targeted therapy and immunotherapy. A major challenge lies in better understanding how melanoma cells evade immune elimination and how tumor growth and metastasis is facilitated by the tumor microenvironment. Here, we show that expression of the cytokine thymic stromal lymphopoietin (TSLP) by epidermal keratinocytes is induced by cutaneous melanoma in both mice and humans. Using genetically engineered models of melanoma and tumor cell grafting combined with TSLP-KO or overexpression, we defined a crosstalk between melanoma cells, keratinocytes, and immune cells in establishing a tumor-promoting microenvironment. Keratinocyte-derived TSLP is induced by signals derived from melanoma cells and subsequently acts via immune cells to promote melanoma progression and metastasis. Furthermore, we show that TSLP signals through TSLP receptor-expressing (TSLPR-expressing) DCs to play an unrecognized role in promoting GATA3+ Tregs expressing a gene signature including ST2, CCR8, ICOS, PD-1, CTLA-4, and OX40 and exhibiting a potent suppressive activity on CD8+ T cell proliferation and IFN-γ production. An analogous population of GATA3-expressing Tregs was also identified in human melanoma tumors. Our study provides insights into the role of TSLP in programming a protumoral immune microenvironment in cutaneous melanoma.
Domaines
Sciences du Vivant [q-bio]Format du dépôt | Fichier |
---|---|
Type de dépôt | Article dans une revue |
Titre |
en
Keratinocyte-derived cytokine TSLP promotes growth and metastasis of melanoma by regulating the tumor-associated immune microenvironment
|
Résumé |
en
Malignant melanoma is a major public health issue displaying frequent resistance to targeted therapy and immunotherapy. A major challenge lies in better understanding how melanoma cells evade immune elimination and how tumor growth and metastasis is facilitated by the tumor microenvironment. Here, we show that expression of the cytokine thymic stromal lymphopoietin (TSLP) by epidermal keratinocytes is induced by cutaneous melanoma in both mice and humans. Using genetically engineered models of melanoma and tumor cell grafting combined with TSLP-KO or overexpression, we defined a crosstalk between melanoma cells, keratinocytes, and immune cells in establishing a tumor-promoting microenvironment. Keratinocyte-derived TSLP is induced by signals derived from melanoma cells and subsequently acts via immune cells to promote melanoma progression and metastasis. Furthermore, we show that TSLP signals through TSLP receptor-expressing (TSLPR-expressing) DCs to play an unrecognized role in promoting GATA3+ Tregs expressing a gene signature including ST2, CCR8, ICOS, PD-1, CTLA-4, and OX40 and exhibiting a potent suppressive activity on CD8+ T cell proliferation and IFN-γ production. An analogous population of GATA3-expressing Tregs was also identified in human melanoma tumors. Our study provides insights into the role of TSLP in programming a protumoral immune microenvironment in cutaneous melanoma.
|
Auteur(s) |
Wenjin Yao
1
, Beatriz German
1
, Dounia Chraa
2
, Antoine Braud
1, 3
, Cecile Hugel
1
, Pierre Meyer
1
, Guillaume Davidson
1
, Patrick Laurette
1
, Gabrielle Mengus
1
, Eric Flatter
1
, Pierre Marschall
1
, Justine Segaud
1
, Marine Guivarch
1
, Pierre Hener
1
, Marie-Christine Birling
4
, Dan Lipsker
3
, Irwin Davidson
1
, Mei Li
1
1
IGBMC -
Institut de Génétique et de Biologie Moléculaire et Cellulaire
( 93800 )
- Parc D'Innovation 1 Rue Laurent Fries - BP 10142 67404 Illkirch Cedex
- France
2
CRCM -
Centre de Recherche en Cancérologie de Marseille
( 179570 )
- 27 bd Leï Roure, BP 300059
13273 Marseille Cedex 09
- France
3
CHU Strasbourg -
Centre Hospitalier Universitaire [Strasbourg]
( 300149 )
- France
4
ICS -
Institut Clinique de la Souris
( 93798 )
- Génopole de Strasbourg 67404 Illkirch Cedex
- France
|
Licence |
Paternité
|
Langue du document |
Anglais
|
Nom de la revue |
|
Vulgarisation |
Non
|
Comité de lecture |
Oui
|
Audience |
Internationale
|
Date de publication |
2022-09-15
|
Domaine(s) |
|
Projet(s) ANR |
|
DOI | 10.1172/jci.insight.161438 |
Pubmed Id | 36107619 |
PubMed Central | PMC9675576 |
Origine :
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