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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 2

Anti-SIRPα synergizes with anti–PD-L1 and anti–4-1BB mAbs and prevents T cell exclusion.

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Anti-SIRPα synergizes with anti–PD-L1 and anti–4-1BB mAbs and prevents T...
(A) Tumor volume in MC38 model of mice treated i.p. triweekly (days 4–28) with control (black, n = 6), MY1-G1 anti-SIRPα (blue, 10 mg/kg, n = 13), anti–PD-L1 (10F-9G2, open green triangle, 6 mg/kg, n = 12), or MY1-G1 plus anti–PD-L1 (filled green triangle, n = 28) mAbs. (B) Survival of untreated naive (black, n = 7) or MC38 tumor-free mice treated with the anti-SIRPα+PD-L1 combination (green, n = 10) and rechallenged with MC38 cells 2 months after first tumor inoculation. (C) Survival in the Hepa1.6 HCC orthotopic model of mice treated i.p. (days 4–28) triweekly with control (black, n = 48), P84 anti-SIRPα (red, 10 mg/kg, n = 48), anti–PD-L1 (open green triangle, 6 mg/kg, n = 14), or P84+anti-PDL-1 (filled green triangle, n = 18) mAbs. Some mice received 2 injections (days 4 and 8) of 3 mg/kg 3H3 (4-1BB agonist; open blue circle, n = 15) alone or in combination with P84 (filled blue circle, n = 15). Three independent experiments are represented. (D) Survival of untreated naive or Hepa1.6-cured mice rechallenged with intrasplenic Hepa 1.6 cells 3 to 4 months after first tumor inoculation. Symbols are the same as in C. (E) Survival of untreated mice implanted with Hepa 1.6 cells in the portal vein after adoptive transfer of 10 × 106 splenocytes or 2.5 × 106 spleen T cells isolated from cured mice in D. (F) Same as in E after adoptive transfer of 200 μL of plasma from PD-L1/SIRPα-cured mice. (G) T cell infiltrates histological quantification in the entire tumor or in the core (50% of the tumor from the center) in the MC38 model 3 weeks after tumor inoculation. Treatment was same as in A. Blue, nucleus; green, CD3. (H) T cell and macrophage infiltrate histological quantification in the Hepa1.6 model 2 weeks after tumor inoculation. FI, fluorescent intensity. Treatment was same as in C. Blue, nucleus; green, CD3; red, F4/80. Original magnification, ×20. *P < 0.05, **P < 0.01 or ##P < 0.01, ***P < 0.005, ****P < 0.001, compared with control group; §§P < 0.01, §§§P < 0.005 for T cell monotherapies compared with combination, unpaired Kruskall-Wallis test, Mann-Whitney U test, or log-rank test or survival.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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