Selective SIRPα blockade reverses tumor T cell exclusion and overcomes cancer immunotherapy resistance
Vanessa Gauttier, … , Bernard Vanhove, Nicolas Poirier
Vanessa Gauttier, … , Bernard Vanhove, Nicolas Poirier
Published October 19, 2020
Citation Information: J Clin Invest. 2020;130(11):6109-6123. https://doi.org/10.1172/JCI135528.
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Research Article Immunology

Selective SIRPα blockade reverses tumor T cell exclusion and overcomes cancer immunotherapy resistance

Abstract

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.

Authors

Vanessa Gauttier, Sabrina Pengam, Justine Durand, Kevin Biteau, Caroline Mary, Aurore Morello, Mélanie Néel, Georgia Porto, Géraldine Teppaz, Virginie Thepenier, Richard Danger, Nicolas Vince, Emmanuelle Wilhelm, Isabelle Girault, Riad Abes, Catherine Ruiz, Charlène Trilleaud, Kerry Ralph, E. Sergio Trombetta, Alexandra Garcia, Virginie Vignard, Bernard Martinet, Alexandre Glémain, Sarah Bruneau, Fabienne Haspot, Safa Dehmani, Pierre Duplouye, Masayuki Miyasaka, Nathalie Labarrière, David Laplaud, Stéphanie Le Bas-Bernardet, Christophe Blanquart, Véronique Catros, Pierre-Antoine Gouraud, Isabelle Archambeaud, Hélène Aublé, Sylvie Metairie, Jean-François Mosnier, Dominique Costantini, Gilles Blancho, Sophie Conchon, Bernard Vanhove, Nicolas Poirier

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Figure 6

Selective targeting of SIRPα sparing SIRPγ/CD47 preserves human T cell responses.

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Selective targeting of SIRPα sparing SIRPγ/CD47 preserves human T cell r...
(A) Representative IFN-γ response of human HLA-A2/melan-A–specific CD8+ T clones stimulated 6 hours with human HLA-A2+ DCs crosspresenting the long peptide melan-A/MART-1 and preincubated for 24 hours with the peptide and 10 μg/mL of different mAbs targeting the SIRPα/SIRPγ/CD47 pathway. (B) Quantification of IFN-γ response as in A normalized to the irrelevant control mAb condition for each DC donor. (C) IL-2 secretion by mouse chimeric thymoma cell line transfected with human CD8 and the HLA-A2/melan-A TCR cultured for 48 hours with human HLA-A2+ DC loaded with melan-A long peptide and cultured with indicated mAbs, as in A. (D) Proliferation of isolated human T cells from human PBMCs cultured with 10 μg/mL of indicated mAbs for 3 days with anti-CD3/anti-CD28–coated beads or (E) for 5 days with allogeneic LPS-matured human DCs. Proliferation measured by H3-thymidine incorporation was normalized under control conditions. (F) Human PBMCs from allogeneic healthy donors were cultured 5 days with indicated mAbs at 10 μg/mL. T cell proliferation was assessed by H3-thymidine incorporation, and TNF-α and IFN-γ secretion was quantified by ELISA and normalized to controls. (G) Human T cell migration across a monolayer of TNF-α–activated endothelial cells with 10 μg/mL of indicated mAbs and CXCL-12 (50 ng/mL) as chemoattractant. The number of transmigrated T cells was determined by flow cytometry after 4 hours and normalized under control conditions. *P < 0.05; **P < 0.01; ****P < 0.001, between indicated conditions, unpaired Kruskall-Wallis test, Mann-Whitney U test. ####P < 0.001, compared with control Ab conditions.