Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell–dependent antitumor effects

Christophe Borg,¹ Magali Terme,¹
Julien Taïeb,¹ Cédric Ménard,¹
Caroline Flament,¹ Caroline Robert,¹
Koji Maruyama,^1,2 Hiro Wakasugi,²
Eric Angevin,¹ Kris Thielemans,³ Axel
Le Cesne,⁴ Véronique Chung-Scott,¹
Vladimir Lazar,¹ Isabelle Tchou,¹
Florent Crépineau,¹ François Lemoine,⁵
Jacky Bernard,⁶ Jonhantan A. Fletcher,⁷
Ali Turhan,⁸ Jean-Yves Blay,⁹ Alain Spatz,¹⁰
Jean-François Emile,¹¹ Michael C. Heinrich,¹²
Salah Mécheri,¹³ Thomas Tursz,¹ and
Laurence Zitvogel¹

 

¹Department of Clinical Biology, Equipe de Recherche Mixte 0208, INSERM,
Institut Gustave Roussy, Villejuif, France. ²Pharmacology and
Immunology Unit, National Cancer Center, Tokyo, Japan. ³Laboratory
of Molecular and Cellular Therapy, Medical School of the Vrije Universiteit
Brussel, Brussels, Belgium. ⁴Department of Medical Oncology,
Institut Gustave Roussy, Villejuif, France. ⁵Centre d’Etudes et de Recherches
en Virologie et Immunologie, Hôpitaux Pitié Salpé trière, Paris, France. ⁶Centre
Jean Godinot, Reims, France. ⁷Harvard Medical School,
Boston, Massachusetts, USA. ⁸Translational Research Unit, Institut
Gustave Roussy, Villejuif, France. ⁹Hospices Civils de Lyon, Hôpital Edouard Hériot, Lyon,
France. ¹⁰Department of Pathology and Translational Research, Institut Gustave
Roussy, Villejuif, France. ¹¹Department of Pathology, Paul Brousse
Hospital, Assistance Publique—Hôpitaux de Paris, Villejuif, France. ¹²Oregon
Health and Science University Cancer Institute, Portland, Oregon, USA. ¹³Immuno-Allergy
Unit, Pasteur Institute, Paris, France.

 

Address correspondence to: Laurence Zitvogel, ERM0208 INSERM, Department
of Clinical Biology, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805
Villejuif Cedex, France. Phone: 33-1-42-11-50-41; Fax: 33-1-42-11-60-94; E-mail: [email protected].

 

Received 2004 January 16; Accepted 2004 June 15.

 

Mutant
isoforms of the KIT or PDGF receptors expressed by gastrointestinal stromal
tumors (GISTs) are considered the therapeutic targets for STI571 (imatinib
mesylate; Gleevec), a specific inhibitor of these tyrosine kinase receptors. Case
reports of clinical efficacy of Gleevec in GISTs lacking the typical receptor
mutations prompted a search for an alternate mode of action. Here we show that
Gleevec can act on host DCs to promote NK cell activation. DC-mediated NK cell
activation was triggered in vitro and in vivo by treatment of DCs with Gleevec
as well as by a loss-of-function mutation of KIT. Therefore, tumors that are
refractory to the antiproliferative effects of Gleevec in vitro responded to
Gleevec in vivo in an NK cell–dependent manner. Longitudinal studies of
Gleevec-treated GIST patients revealed a therapy-induced increase in IFN-γ production by NK cells, correlating with an enhanced antitumor
response. These data point to a novel mode of antitumor action for Gleevec.

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