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Regulation of CD4+NKG2D+ Th1 Cells in Patients with Metastatic Melanoma Treated with Sorafenib: Role of IL-15Rα and NKG2D Triggering

Ana Romero 1, 2 Nathalie Chaput 1, 3, 2 Vichnou Poirier-Colame 1, 3, 2 Sylvie Rusakiewicz 3, 1, 2 Nicolas Jacquelot 2, 3, 1 Kariman Chaba 1, 2 Erwan Mortier 4 Yannick Jacques 4 Sophie Caillat-Zucman 5 Caroline Flament 1, 2 Anne Caignard 5 Meriem Messaoudene 5 Anne Aupérin 6, 1 Philippe Vielh 7, 1 Philippe Dessen 8, 1, 9 Camillo Porta 10 Christine Mateus 11, 1 Maha Ayyoub 12 Danila Valmori 12 Alexander Eggermont 1 Caroline Robert 1, 11 Laurence Zitvogel 3, 1, 2, 13, *
* Corresponding author
1 IGR - Institut Gustave Roussy
2 UMR 1015 - Immunologie des tumeurs et immunothérapie
3 CIC 1428 , CBT 507 - Centre d'Investigation Clinique en Biotherapie des cancers
4 CRCNA - Centre de Recherche en Cancérologie Nantes-Angers
5 IC UM3 (UMR 8104 / U1016) - Institut Cochin
6 SBE - Service de biostatistique et d'épidémiologie
7 Laboratoire de recherche translationnelle
Direction de la recherche [Gustave Roussy]
8 U1170 Inserm - Hématopoïèse normale et pathologique
9 UMR 8200 - Stabilité Génétique et Oncogenèse
10 IRCCS San Matteo Hospital Foundation & University of Pavia
11 Service de dermatologie
Département de médecine oncologique [Gustave Roussy]
12 UNICANCER/ICO - Institut de Cancérologie de l'Ouest [Angers/Nantes]
13 UP11 - Université Paris-Sud - Paris 11
Abstract : Beyond cancer-cell intrinsic factors, the immune status of the host has a prognostic impact on patients with cancer and influences the effects of conventional chemotherapies. Metastatic melanoma is intrinsically immunogenic, thereby facilitating the search for immune biomarkers of clinical responses to cytotoxic agents. Here, we show that a multi-tyrosine kinase inhibitor, sorafenib, upregulates interleukin (IL)-15Rα in vitro and in vivo in patients with melanoma, and in conjunction with natural killer (NK) group 2D (NKG2D) ligands, contributes to the Th1 polarization and accumulation of peripheral CD4+NKG2D+ T cells. Hence, the increase of blood CD4+NKG2D+ T cells after two cycles of sorafenib (combined with temozolomide) was associated with prolonged survival in a prospective phase I/II trial enrolling 63 patients with metastatic melanoma who did not receive vemurafenib nor immune checkpoint–blocking antibodies. In contrast, in metastatic melanoma patients treated with classical treatment modalities, this CD4+NKG2D+ subset failed to correlate with prognosis. These findings indicate that sorafenib may be used as an "adjuvant" molecule capable of inducing or restoring IL-15Rα/IL-15 in tumors expressing MHC class I–related chain A/B (MICA/B) and on circulating monocytes of responding patients, hereby contributing to the bioactivity of NKG2D+ Th1 cells.
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INSERM | ICO | UNAM | FNCLCC | UNIV-PARIS5 | USPC | CNRS | IGR | UNIV-PARIS | UP-SANTE | POLITIQUES-PUBLIQUES | GS-HEALTH-DRUG-SCIENCES | CRCNA

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Ana Romero, Nathalie Chaput, Vichnou Poirier-Colame, Sylvie Rusakiewicz, Nicolas Jacquelot, et al.. Regulation of CD4+NKG2D+ Th1 Cells in Patients with Metastatic Melanoma Treated with Sorafenib: Role of IL-15Rα and NKG2D Triggering. Cancer Research, American Association for Cancer Research, 2014, 74 (1), pp.68. ⟨10.1158/0008-5472.CAN-13-1186⟩. ⟨inserm-02442721⟩

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