Tumor-derived granzyme B-expressing neutrophils acquire antitumor potential after lipid A treatment
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Amandine Martin1,2,*, Cédric Seignez1,2,*, Cindy Racoeur1,2, Nicolas Isambert1,2,3, Nesrine Mabrouk1,2, Alessandra Scagliarini1,2, Sylvie Reveneau1,2, Laurent Arnould3, Ali Bettaieb1,2, Jean-François Jeannin1,2 and Catherine Paul1,2
1Laboratoire d'Immunologie et Immunothérapie des Cancers, EPHE, PSL Research University, 75000 Paris, France
2LIIC, EA7269, Université de Bourgogne Franche Comté, 21000 Dijon, France
3Centre Georges-François Leclerc, Dijon, F-21000, France
*These authors contributed equally to this work
Catherine Paul, email: [email protected]
Keywords: tumor-associated neutrophils; granzyme B; colon cancer; immune response; lipid A
Received: September 19, 2017 Accepted: April 21, 2018 Published: June 19, 2018
Neutrophils are known to possess both pro- and anti-tumor properties, a feature that could be related to the diversity and plasticity of these cells. Here we explored the hypothesis that under an appropriate environment and stimuli, neutrophils could induce an effective response against tumor cells. In a rat and mouse models, we show that a substantial amount of colon tumor associated-neutrophils (TAN) expressed the cytolytic enzyme granzyme B, which is absent in spleen or blood circulating neutrophils. This TAN population was also found into tumors of patients with colon cancer. Tumor neutrophil infiltration was correlated with an increase of chemokines known to attract neutrophils in both rat models and patients. These cells were involved in a Lipid A analog-mediated colon tumor regression. Mechanistically, treating the rats with the Lipid A analog triggered granzyme B release from neutrophils in tumor cell vicinity, which was correlated to tumor regression. Alteration of granzyme B function in tumor cells decreased the cytotoxic effect of Lipid A in rat and mouse models. Granzyme B expression in neutrophils could be induced by the lipid A analog but also by some of the cytokines that were detected in the tumor microenvironment. These results identify a subpopulation of neutrophils expressing granzyme B that can act as a key player of lipid A-mediated colon cancer regression in rat and mouse models and the molecular mechanisms involved may provide novel approaches for human therapeutic intervention.
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