Selective SIRPα blockade reverses tumor T cell exclusion and overcomes cancer immunotherapy resistance
Vanessa Gauttier
(1)
,
Sabrina Pengam
(1)
,
Justine Durand
(1)
,
Kevin Biteau
(1)
,
Caroline Mary
(1)
,
Aurore Morello
(1)
,
Mélanie Néel
(2, 3, 4)
,
Georgia Porto
(2, 4)
,
Géraldine Teppaz
(1)
,
Virginie Thepenier
(1)
,
Richard Danger
(2, 3, 4)
,
Nicolas Vince
(2, 4)
,
Emmanuelle Wilhelm
(1)
,
Isabelle Girault
(1)
,
Riad Abes
(1)
,
C Ruiz
(1)
,
Charlène Trilleaud
(1, 2, 4)
,
Kerry Ralph
(5)
,
E Sergio Trombetta
(5)
,
Alexandra Garcia
(2, 4, 3)
,
Virginie Vignard
(3)
,
Bernard Martinet
(2, 4)
,
Alexandre Glemain
(2, 4)
,
Sarah Bruneau
(2, 4)
,
Fabienne Haspot
(2, 4)
,
Safa Dehmani
(2, 4)
,
Pierre Duplouye
(2, 4)
,
Masayuki Miyasaka
(6)
,
Nathalie Labarrière
(7)
,
David Laplaud
(2, 4)
,
Stephanie Le Bas-Bernardet
(2, 4)
,
Christophe Blanquart
(8, 9)
,
Véronique Catros
(10, 11, 12)
,
Pierre-Antoine Gouraud
(2, 4)
,
Isabelle Archambeaud
(13)
,
Hélène Aublé
(13)
,
Sylvie Métairie
(13)
,
J.-F. Mosnier
(2, 4)
,
D Costantini
(1)
,
Gilles Blancho
(2, 4)
,
Sophie Conchon
(2, 4)
,
Bernard Vanhove
(1)
,
Nicolas Poirier
(1)
1
OSE Immunotherapeutics [Nantes, France]
2 U1064 Inserm - CRTI - Centre de Recherche en Transplantation et Immunologie
3 CHU Nantes - Centre Hospitalier Universitaire de Nantes = Nantes University Hospital
4 ITUN - Institut de transplantation urologie-néphrologie
5 Boehringer Ingelheim Pharma GmbH & Co. KG
6 Osaka University
7 CRCINA-ÉQUIPE 3 - Anti-Tumor Immunosurveillance and Immunotherapy
8 UN - Université de Nantes
9 CRCINA-ÉQUIPE 4 - Immunogenic Cell Death and Mesothelioma Therapy
10 NuMeCan - Nutrition, Métabolismes et Cancer
11 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Ponchaillou]
12 CRB Santé - Centre de Ressources Biologiques Santé
13 IMAD - Institut des maladies de l'appareil digestif [Nantes]
2 U1064 Inserm - CRTI - Centre de Recherche en Transplantation et Immunologie
3 CHU Nantes - Centre Hospitalier Universitaire de Nantes = Nantes University Hospital
4 ITUN - Institut de transplantation urologie-néphrologie
5 Boehringer Ingelheim Pharma GmbH & Co. KG
6 Osaka University
7 CRCINA-ÉQUIPE 3 - Anti-Tumor Immunosurveillance and Immunotherapy
8 UN - Université de Nantes
9 CRCINA-ÉQUIPE 4 - Immunogenic Cell Death and Mesothelioma Therapy
10 NuMeCan - Nutrition, Métabolismes et Cancer
11 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Ponchaillou]
12 CRB Santé - Centre de Ressources Biologiques Santé
13 IMAD - Institut des maladies de l'appareil digestif [Nantes]
Richard Danger
- Fonction : Auteur
- PersonId : 767374
- ORCID : 0000-0002-5058-795X
- IdRef : 158591453
Nicolas Vince
- Fonction : Auteur
- PersonId : 1131457
- IdHAL : nicolas-vince
Bernard Martinet
- Fonction : Auteur
- PersonId : 755880
- ORCID : 0000-0001-6370-7810
Nathalie Labarrière
- Fonction : Auteur
- PersonId : 182569
- IdHAL : nathalie-labarriere
- ORCID : 0000-0002-1407-6546
- IdRef : 127025154
Christophe Blanquart
- Fonction : Auteur
- PersonId : 182432
- IdHAL : christophe-blanquart
- ORCID : 0000-0002-0917-3747
- IdRef : 079241417
Gilles Blancho
- Fonction : Auteur
- PersonId : 767373
- ORCID : 0000-0003-0356-5069
- IdRef : 080126626
Résumé
T cell exclusion causes resistance to cancer immunotherapies via immune checkpoint blockade (ICB). Myeloid cells contribute to resistance by expressing signal regulatory protein-α (SIRPα), an inhibitory membrane receptor that interacts with ubiquitous receptor CD47 to control macrophage phagocytosis in the tumor microenvironment. Although CD47/SIRPα-targeting drugs have been assessed in preclinical models, the therapeutic benefit of selectively blocking SIRPα, and not SIRPγ/CD47, in humans remains unknown. We report a potent synergy between selective SIRPα blockade and ICB in increasing memory T cell responses and reverting exclusion in syngeneic and orthotopic tumor models. Selective SIRPα blockade stimulated tumor nest T cell recruitment by restoring murine and human macrophage chemokine secretion and increased anti-tumor T cell responses by promoting tumor-antigen crosspresentation by dendritic cells. However, nonselective SIRPα/SIRPγ blockade targeting CD47 impaired human T cell activation, proliferation, and endothelial transmigration. Selective SIRPα inhibition opens an attractive avenue to overcoming ICB resistance in patients with elevated myeloid cell infiltration in solid tumors.