Abstract 4868: Tyrosine kinase-dependent modulation of tumor infiltrating immune cells in melanoma
Authors: Babdor Joël , Fricot Aurélie , Dussiot Michaël , Hebert Lucile , Dubreuil Patrice , Moura Ivan Cruz , Maciel Thiago Trovati , Hermine Olivier 
Published: July 2016

Abstract
Melanoma causes the greatest morbidity and mortality of all skin cancers and often harbors amplifications or activating mutations in KIT, a type III transmembrane receptor tyrosine kinase (RTK) involved in cancer cell growth, migration, invasion and metastasis. At present, no treatment that provide either sufficient response rates or a significant prolongation of overall survival are available for melanoma. In the last decade, several inhibitors of RTK (RTKi) have been developed for the treatment of cancer, however, a number of short-comings was observed. Therefore, novel TK inhibitors with improved selectivity were developed for the treatment of diseases associated with KIT activation. Masitinib (AB1010), a RTKi capable of blocking selectively KIT, is one such new drug. Using B16 melanoma subcutaneous graft on C57Bl6 mice, we demonstrate that Masitinib is able to limit tumor growth in vivo and increase mice survival. This anti-tumoral effect was not observed for other RTKi targeting KIT. Suprisingly, Masitinib has no effect on melanoma proliferation in vitro, suggesting instead that modulation on tumor environment takes place. Indeed, mast cells that accumulate in the tumors secrete several biologically active factors involved in the modulation of tumor growth. In vivo, Masitinib treatment completely abrogates mast cell maturation and migration resulting in decreased tumor invasion and down-regulation of several angiogenic factors. Using a mouse line deficient for mast cells (Wsh/Wsh), we confirmed that Masitinib effect is in part dependent of its inhibition on mast cell migration and maturation. Indeed, additional effect occurs on macrophage polarization leaning from “tolerogenic” toward “anti-tumoral” phenotype. Furthermore, in vivo macrophage depletion favored tumor promotion and reverses Masitinib effect on tumor growth. The results provided by this study suggest that Masitinib may be a useful therapy on melanoma by its dual role on tumor environment. It can block mast cell maturation and infiltration in the tumor site, avoiding the angiogenic effects of mast cells. It can revert tumor tolerent macrophage status leading to an increased inflammatory activity within the tumor microenvironment.
These effects are not observed only on melanoma, but also on other types of cancer, suggesting the cellular mechanisms triggered by Masitinib occur in various tumoral process. For instance, a phase III clinical trial with Masitinib as GIST treatment is currently ongoing.
Citation Format: Joël Babdor, Aurélie Fricot, Michaël Dussiot, Lucile Hebert, Patrice Dubreuil, Ivan Cruz Moura, Thiago Trovati Maciel, Olivier Hermine. Tyrosine kinase-dependent modulation of tumor infiltrating immune cells in melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4868.