The accrual of myeloid-derived suppressor cells (MDSCs) represents a major obstacle to effective immunotherapy in cancer patients, but the mechanisms underlying this process in the human setting remain elusive. Here, we describe a set of microRNAs (miR-146a, miR-155, miR-125b, miR-100, let-7e, miR-125a, miR-146b, miR-99b) that are associated with MDSCs and with resistance to treatment with immune checkpoint inhibitors in melanoma patients. The miRs were identified by transcriptional analyses as being responsible for the conversion of monocytes into MDSCs (CD14+HLA-DRneg cells) mediated by melanoma extracellular vesicles (EVs) and were shown to recreate MDSC features upon transfection. In melanoma patients, these miRs are increased in circulating CD14+ monocytes, plasma and tumor samples, where they correlate with the myeloid cell infiltrate. In plasma, their baseline level clusters with the clinical efficacy of CTLA-4 or PD-1 blockade. Hence, MDSC-related miRs represent an indicator of MDSC activity in cancer patients and a potential blood marker of a poor immunotherapy outcome.
Tumor-derived microRNAs induce myeloid suppressor cells and predict immunotherapy resistance in melanoma / V. Huber, V. Vallacchi, V. Fleming, X. Hu, A. Cova, M. Dugo, E. Shahaj, R. Sulsenti, E. Vergani, P. Filipazzi, A. De Laurentiis, L. Lalli, L. Di Guardo, R. Patuzzo, B. Vergani, E. Casiraghi, M. Cossa, A. Gualeni, V. Bollati, F. Arienti, F. De Braud, L. Mariani, A. Villa, P. Altevogt, V. Umansky, M. Rodolfo, L. Rivoltini. - In: THE JOURNAL OF CLINICAL INVESTIGATION. - ISSN 1558-8238. - 128:12(2018 Dec 03), pp. 5505-5516. [10.1172/JCI98060]
Tumor-derived microRNAs induce myeloid suppressor cells and predict immunotherapy resistance in melanoma
E. Casiraghi;V. Bollati;F. De Braud;
2018
Abstract
The accrual of myeloid-derived suppressor cells (MDSCs) represents a major obstacle to effective immunotherapy in cancer patients, but the mechanisms underlying this process in the human setting remain elusive. Here, we describe a set of microRNAs (miR-146a, miR-155, miR-125b, miR-100, let-7e, miR-125a, miR-146b, miR-99b) that are associated with MDSCs and with resistance to treatment with immune checkpoint inhibitors in melanoma patients. The miRs were identified by transcriptional analyses as being responsible for the conversion of monocytes into MDSCs (CD14+HLA-DRneg cells) mediated by melanoma extracellular vesicles (EVs) and were shown to recreate MDSC features upon transfection. In melanoma patients, these miRs are increased in circulating CD14+ monocytes, plasma and tumor samples, where they correlate with the myeloid cell infiltrate. In plasma, their baseline level clusters with the clinical efficacy of CTLA-4 or PD-1 blockade. Hence, MDSC-related miRs represent an indicator of MDSC activity in cancer patients and a potential blood marker of a poor immunotherapy outcome.File | Dimensione | Formato | |
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