Tumor-derived microRNAs induce myeloid suppressor cells and predict immunotherapy resistance in melanoma

Veronica Huber, Viviana Vallacchi, Viktor Fleming, Xiaoying Hu, Agata Cova, Matteo Dugo, Eriomina Shahaj, Roberta Sulsenti, Elisabetta Vergani, Paola Filipazzi, Angela De Laurentiis, Luca Lalli, Lorenza Di Guardo, Roberto Patuzzo, Barbara Vergani, Elena Casiraghi, Mara Cossa, Ambra Gualeni, Valentina Bollati, Flavio ArientiFilippo De Braud, Luigi Mariani, Antonello Villa, Peter Altevogt, Viktor Umansky, Monica Rodolfo, Licia Rivoltini

Research output: Contribution to journalArticle

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 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 were increased in circulating CD14+ monocytes, plasma, and tumor samples, where they correlated with the myeloid cell infiltrate. In plasma, their baseline levels clustered with the clinical efficacy of CTLA-4 or programmed cell death protein 1 (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.

Original languageEnglish
Pages (from-to)5505-5516
Number of pages12
JournalJournal of Clinical Investigation
Volume128
Issue number12
DOIs
Publication statusPublished - Dec 3 2018

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Myeloid Cells
MicroRNAs
Immunotherapy
Melanoma
Neoplasms
Programmed Cell Death 1 Receptor
Monocytes
Transfection
Myeloid-Derived Suppressor Cells

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Tumor-derived microRNAs induce myeloid suppressor cells and predict immunotherapy resistance in melanoma. / Huber, Veronica; Vallacchi, Viviana; Fleming, Viktor; Hu, Xiaoying; Cova, Agata; Dugo, Matteo; Shahaj, Eriomina; Sulsenti, Roberta; Vergani, Elisabetta; Filipazzi, Paola; De Laurentiis, Angela; Lalli, Luca; Di Guardo, Lorenza; Patuzzo, Roberto; Vergani, Barbara; Casiraghi, Elena; Cossa, Mara; Gualeni, Ambra; Bollati, Valentina; Arienti, Flavio; De Braud, Filippo; Mariani, Luigi; Villa, Antonello; Altevogt, Peter; Umansky, Viktor; Rodolfo, Monica; Rivoltini, Licia.

In: Journal of Clinical Investigation, Vol. 128, No. 12, 03.12.2018, p. 5505-5516.

Research output: Contribution to journalArticle

Huber, V, Vallacchi, V, Fleming, V, Hu, X, Cova, A, Dugo, M, Shahaj, E, Sulsenti, R, Vergani, E, Filipazzi, P, De Laurentiis, A, Lalli, L, Di Guardo, L, Patuzzo, R, Vergani, B, Casiraghi, E, Cossa, M, Gualeni, A, Bollati, V, Arienti, F, De Braud, F, Mariani, L, Villa, A, Altevogt, P, Umansky, V, Rodolfo, M & Rivoltini, L 2018, 'Tumor-derived microRNAs induce myeloid suppressor cells and predict immunotherapy resistance in melanoma', Journal of Clinical Investigation, vol. 128, no. 12, pp. 5505-5516. https://doi.org/10.1172/JCI98060
Huber, Veronica ; Vallacchi, Viviana ; Fleming, Viktor ; Hu, Xiaoying ; Cova, Agata ; Dugo, Matteo ; Shahaj, Eriomina ; Sulsenti, Roberta ; Vergani, Elisabetta ; Filipazzi, Paola ; De Laurentiis, Angela ; Lalli, Luca ; Di Guardo, Lorenza ; Patuzzo, Roberto ; Vergani, Barbara ; Casiraghi, Elena ; Cossa, Mara ; Gualeni, Ambra ; Bollati, Valentina ; Arienti, Flavio ; De Braud, Filippo ; Mariani, Luigi ; Villa, Antonello ; Altevogt, Peter ; Umansky, Viktor ; Rodolfo, Monica ; Rivoltini, Licia. / Tumor-derived microRNAs induce myeloid suppressor cells and predict immunotherapy resistance in melanoma. In: Journal of Clinical Investigation. 2018 ; Vol. 128, No. 12. pp. 5505-5516.
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AU - Huber, Veronica

AU - Vallacchi, Viviana

AU - Fleming, Viktor

AU - Hu, Xiaoying

AU - Cova, Agata

AU - Dugo, Matteo

AU - Shahaj, Eriomina

AU - Sulsenti, Roberta

AU - Vergani, Elisabetta

AU - Filipazzi, Paola

AU - De Laurentiis, Angela

AU - Lalli, Luca

AU - Di Guardo, Lorenza

AU - Patuzzo, Roberto

AU - Vergani, Barbara

AU - Casiraghi, Elena

AU - Cossa, Mara

AU - Gualeni, Ambra

AU - Bollati, Valentina

AU - Arienti, Flavio

AU - De Braud, Filippo

AU - Mariani, Luigi

AU - Villa, Antonello

AU - Altevogt, Peter

AU - Umansky, Viktor

AU - Rodolfo, Monica

AU - Rivoltini, Licia

PY - 2018/12/3

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N2 - 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 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 were increased in circulating CD14+ monocytes, plasma, and tumor samples, where they correlated with the myeloid cell infiltrate. In plasma, their baseline levels clustered with the clinical efficacy of CTLA-4 or programmed cell death protein 1 (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.

AB - 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 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 were increased in circulating CD14+ monocytes, plasma, and tumor samples, where they correlated with the myeloid cell infiltrate. In plasma, their baseline levels clustered with the clinical efficacy of CTLA-4 or programmed cell death protein 1 (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.

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