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 5

Anti-SIRPα mAb reinstates myeloid cell chemokine secretion and human T cell migration.

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Anti-SIRPα mAb reinstates myeloid cell chemokine secretion and human T c...
(A) CCL4 (n = 6) chemokine secretion of human macrophages cultured for 24 hours on normal or CD47-coated plates with or without anti-SIRPα mAb (OSE-172, 10μg/mL). (B) CCL4 secretion of human monocytes cultured 24 hours in contact with different human tumor cell lines and 10 μg/mL of anti-SIRPα mAb (OSE-172) or irrelevant control Ab (1 representative donor of n = 5). (C) Immunodeficient NSG-SGM3 mice (expressing human IL3, GM-CSF and SCF) humanized with 30 × 106 human PBMCs injected i.p. were treated i.p. on day 4 with 10 mg/kg of selective anti-SIRPα mAb (OSE-172, n = 10), a nonselective anti-SIRPα/γ mAb (Kwar23, n = 3), or an irrelevant control mAb (n = 11). Intradermal injection in the ear of autologous human macrophages (generated in vitro from blood monocytes cultured 5 days with 100 ng/mL M-CSF) was performed on day 5. (D) The ear was collected for immunohistological analysis 6 hours after macrophage injection. T cell infiltration was quantified per mm3 of tissue using quantification of CD3+ cells on serial sections from each individual mouse. *P < 0.05; **P < 0.01, unpaired Mann-Whitney U test. (E) Representative example of human CD3 staining (green) and nucleus (blue) from each group in D. (F) A549 NSCLC cell line was cultured with human monocytes, MRC-5 fibroblasts, and indicated monoclonal antibodies at 10 μg/mL. After 3 days, human T lymphocytes were added on established spheroids and cultured for an additional 3 days. (G) Spheroids were fixed on day 6 and stained with anti-human CD3 Ab; T cell invasive index was calculated according to frequency and distance from periphery of CD3+ cells. (H) Representative example of human CD3 staining (green) and nucleus (blue) from each group in G. Original magnification, ×100 (E); ×200 (H). **P < 0.01; ****P < 0.0001, Kruskal-Wallis and Dunn’s multiple comparisons tests.