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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 Article has an altmetric score of 101

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

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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 4

Anti-SIRPα mAb reinvigorates myeloid cells in the human TME.

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Anti-SIRPα mAb reinvigorates myeloid cells in the human TME.
(A) Fresh h...
(A) Fresh human surgical tumor explants (HCC, n = 7; RCC, n = 2; CRC, n = 1; PDAC, n = 1) dissociated in small organoids by enzymatic and mechanical digestion or cells from Meso (n = 7) were cultured for 48 hours with 10 μg/mL of selective anti-SIRPα (OSE-172) or irrelevant control mAbs. Transcriptomic analysis was performed using the Human PCIP panel (NanoString). (B) nSolver relative gene expression analysis and volcano plot representation using the Benjamini-Hochberg method to adjust the P value and the tumor origin as a confounding factor. (C) Heatmap representation of significantly overexpressed genes after treatment with anti-SIRPα (left). Gene expression signatures of main function identified in overexpressed genes as annotated by NanoString (right). (D) Myeloid cells from ovarian cancer ascites were isolated after Ficoll separation of ascites fluid and magnetic separation of CD14+ cells. Isolated myeloid cells were cultured for 48 hours with 10 μg/mL of selective anti-SIRPα (OSE-172) or irrelevant control mAbs. Transcriptomic analysis was performed using the Myeloid Innate Immunity panel_v2 (NanoString). (E) GSEA of functional gene expression signatures identified by nSolver analysis as significantly overexpressed after anti-SIRPα treatment. (F) STRING protein-protein network analysis of the top 100 most overexpressed genes after anti-SIRPα treatment (left). Unsupervised heatmap representation of individual patient gene expression from the 2 main functional clusters (chemokine and cytokines) identified by STRING analysis (right). *P < 0.05; ****P < 0.0001, paired Mann-Whitney U test.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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