Adenosine-Deaminase-Acting-on-RNA-1 Facilitates T-cell Migration toward Human Melanoma Cells

Naama Margolis, Hanna Moalem, Tomer Meirson, Gilli Galore-Haskel, Ettai Markovits, Erez N. Baruch, Bella Vizel, Avner Yeffet, Julia Kanterman-Rifman, Assaf Debby, Michal J. Besser, Jacob Schachter, Gal Markel

Research output: Contribution to journalArticlepeer-review

Abstract

The effect of tumor/T-cell interactions on subsequent immune infiltration is undefined. Here, we report that preexposure of melanoma cells to cognate T cells enhanced the chemotaxis of new T cells in vitro. The effect was HLA class I–restricted and IFNg - dependent, as it was abolished by b2M-knockdown, MHC-blocking antibodies, JAK1 inhibitors, JAK1-silencing and IFNgR1-blocking antibodies. RNA sequencing (RNA-seq) of 73 melanoma metastases showed a significant correlation between the interferon-inducible p150 isoform of adenosine-deaminase-acting-on-RNA-1 (ADAR1) enzyme and immune infiltration. Consistent with this, cocultures of cognate melanoma/T-cell pairs led to IFNg -dependent induction of ADAR1-p150 in the melanoma cells, as visualized in situ using dynamic cell blocks, in ovo using fertilized chick eggs, and in vitro with Western blots. ADAR1 staining and RNA-seq in patient-derived biopsies following immunotherapy showed a rise in ADAR1-p150 expression concurrently with CD8þ cell infiltration and clinical response. Silencing ADAR1-p150 abolished the IFNg-driven enhanced T-cell migration, confirming its mechanistic role. Silencing and overexpression of the constitutive isoform of ADAR1, ADAR1-p110, decreased and increased T-cell migration, respectively. Chemokine arrays showed that ADAR1 controls the secretion of multiple chemokines from melanoma cells, probably through microRNA-mediated regulation. Chemokine receptor blockade eliminated the IFNg-driven T-cell chemotaxis. We propose that the constitutive ADAR1 downregulation observed in melanoma contributes to immune exclusion, whereas antigen-specific T cells induce ADAR1-p150 by releasing IFNg, which can drive T-cell infiltration.

Original languageEnglish
Pages (from-to)1127-1140
Number of pages14
JournalCancer immunology research
Volume10
Issue number9
DOIs
StatePublished - Sep 2022

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