TY - JOUR
T1 - Regulation of CD4+NKG2D+ Th1 cells in patients with metastatic melanoma treated with sorafenib
T2 - Role of IL-15Rα and NKG2D triggering
AU - Romero, Ana I.
AU - Chaput, Nathalie
AU - Poirier-Colame, Vichnou
AU - Rusakiewicz, Sylvie
AU - Jacquelot, Nicolas
AU - Chaba, Kariman
AU - Mortier, Erwan
AU - Jacques, Yannick
AU - Caillat-Zucman, Sophie
AU - Flament, Caroline
AU - Caignard, Anne
AU - Messaoudene, Meriem
AU - Aupérin, Anne
AU - Vielh, Philippe
AU - Dessen, Philippe
AU - Porta, Camillo
AU - Mateus, Christine
AU - Ayyoub, Maha
AU - Valmori, Danila
AU - Eggermont, Alexander
AU - Robert, Caroline
AU - Zitvogel, Laurence
PY - 2014/1/1
Y1 - 2014/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84892779481&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-13-1186
DO - 10.1158/0008-5472.CAN-13-1186
M3 - Article
C2 - 24197135
AN - SCOPUS:84892779481
SN - 0008-5472
VL - 74
SP - 68
EP - 80
JO - Cancer Research
JF - Cancer Research
IS - 1
ER -