Tumor-derived microRNAs induce myeloid suppressor cells and predict immunotherapy resistance in melanoma
Veronica Huber, … , Monica Rodolfo, Licia Rivoltini
Veronica Huber, … , Monica Rodolfo, Licia Rivoltini
Published September 27, 2018
Citation Information: J Clin Invest. 2018;128(12):5505-5516. https://doi.org/10.1172/JCI98060.
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Research Article Immunology Oncology

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

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.

Authors

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 Arienti, Filippo De Braud, Luigi Mariani, Antonello Villa, Peter Altevogt, Viktor Umansky, Monica Rodolfo, Licia Rivoltini

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Figure 3

miR regulation in EV-MDSCs.

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miR regulation in EV-MDSCs. (A) Volcano plot of the miRs regulated in EV...
(A) Volcano plot of the miRs regulated in EV-MDSCs (n = 5 HD) compared with untreated monocytes based on microarray results, identification strategy of MDSC-miRs, and relative expression of selected miRs in EV-MDSCs compared with untreated monocytes assessed by qPCR in a representative HD. (B) Expression of MDSC-miRs in f1 and f2 plasma EVs of melanoma patients (n = 16). Box and whiskers (Tukey’s test). (C) Monocytes from HD transfected with MDSC-miR mimics (MmiRs) modulate HLA-DRA, IL6, and CCL2 gene expression compared with monocytes treated with scrambled control used as calibrator. (D) Immunosuppressive activity of mono+MmiRs on autologous activated CFSE-labeled T cells, as evaluated by CD25 expression and proliferation (percentage is indicated, left), and release of IFN-γ and TNF-α (right). (E) Loss of immunosuppressive activity of monocytes from a melanoma patient transfected with miR inhibitors (ImiRs) prior to coincubation with autologous activated CFSE-labeled T cells, as evaluated by flow cytometry (left) and cytokine release (right). (F) Expression of MDSC-miRs in CD14+ cells isolated from PBMCs of melanoma patients (n = 31) and HD (n = 15). AU, arbitrary units. P < 0.05, paired Student’s t test (A, C) and Mann-Whitney U test (F). *P < 0.05; **P < 0.01, paired Student’s t test (B, D, E). Results are representative of 5 (C), 4 (D), and 3 (E) experiments.