Regulation of CD4+NKG2D+ Th1 cells in patients with metastatic melanoma treated with sorafenib: Role of IL-15Rα and NKG2D triggering

Ana I. Romero, Nathalie Chaput, Vichnou Poirier-Colame, Sylvie Rusakiewicz, Nicolas Jacquelot, Kariman Chaba, Erwan Mortier, Yannick Jacques, Sophie Caillat-Zucman, Caroline Flament, Anne Caignard, Meriem Messaoudene, Anne Aupérin, Philippe Vielh, Philippe Dessen, Camillo Porta, Christine Mateus, Maha Ayyoub, Danila Valmori, Alexander EggermontCaroline Robert, Laurence Zitvogel

Research output: Contribution to journalArticlepeer-review

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 MHCclass I-related chain A/B (MICA/B) and on circulating monocytes of responding patients, hereby contributing to the bioactivity of NKG2D+ Th1 cells.

Original languageEnglish
Pages (from-to)68-80
Number of pages13
JournalCancer Research
Volume74
Issue number1
DOIs
Publication statusPublished - Jan 1 2014

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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