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 1

Anti-SIRPα monotherapy efficacy in orthotopic syngeneic tumor models.

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Anti-SIRPα monotherapy efficacy in orthotopic syngeneic tumor models. (A...
(A) Primary tumor volume and (B) lung metastasis count in the 4T1 triple-negative breast orthotopic tumor model (0.25 × 106 cells injected in the mammary fat gland) of mice treated i.p. with a control mAb (black, n = 7), P84 (red, n = 8), or MY1-G1 (blue, n = 6) anti-SIRPα antagonist mAbs at 10 mg/kg 3 times from day 4 to day 18. (C) Tumor-infiltrating frequencies among live cells and peripheral leukocyte phenotype modification after treatment with P84 (red, n = 7) or control (black, n = 9) mAbs 15 days after tumor implantation. (D) Same protocols and symbols as in A, but a surgical resection of the primary tumor was performed 13 days after tumor implantation and the survival of mice (n = 7 per group) was analyzed. (E) Survival of WT (black, n = 23) and SIRPα mutant (purple, n = 11) untreated mice injected on day 0 in the pleural cavity with AK7 mesothelioma tumor cells (3 × 106). Some WT mice were also treated i.p. with the MY-1-mG1 anti-SIRPα mAb (blue, n = 16) from day 4 to day 32 at 10 mg/kg 3 times a week. Three independent experiments were performed. (F) Cured-SIRPα mutant mice from the AK7 model were rechallenged i.p. with a new load of 3 × 106 AK7 cells (n = 6). The same injection was performed in untreated WT mice as control (n = 7). *P < 0.05; **P < 0.01; ***P < 0.005, compared with control group; #P < 0.05 for P84 and MY-1 comparison, unpaired Mann-Whitney U test or log-rank for survival.