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 December 3, 2018; First 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 5

MDSC-miRs are expressed in tumor specimens and monocytes of melanoma patients.

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MDSC-miRs are expressed in tumor specimens and monocytes of melanoma pat...
(A) Correlation matrix of the expression levels of MDSC-miRs and CD163, CD14, CD209, ITGAM, CD33, CD68, CD3D, CD4, CD8A, PMEL, TYR, and MLANA in metastatic melanoma specimens (n = 58); PMEL, TYR, MLANA, miR-21, and miR-211 are used as unrelated controls. r values from univariate Spearman’s analysis in correlations with P < 0.05. (B) Immunostaining of CD163 infiltrate in melanoma (left panel) and correlation of the quantified CD163 signal with the expression levels of MDSC-miRs (right panel), as determined by qPCR (n = 20). (C) ISH images showing the expression of miR-146a, miR-100, miR-125b, and miR-155 in representative tumor sections. miR signals appear as brown dots localized both in CD163+ infiltrating cells and in melanoma cells. Scale bars: 100 μm. Representative images are shown in B and C.