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

Author:

Margolis Naama12ORCID,Moalem Hanna12ORCID,Meirson Tomer13ORCID,Galore-Haskel Gilli14ORCID,Markovits Ettai12ORCID,Baruch Erez N.12ORCID,Vizel Bella12ORCID,Yeffet Avner5ORCID,Kanterman-Rifman Julia5ORCID,Debby Assaf67ORCID,Besser Michal J.12ORCID,Schachter Jacob1ORCID,Markel Gal123ORCID

Affiliation:

1. 1Ella Lemelbaum Institute for Immuno-Oncology and Melanoma, Sheba Medical Center, Ramat Gan, Israel.

2. 2Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv-Yafo, Israel.

3. 3Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel.

4. 44C Biomed Industries Ltd., Netanya, Israel.

5. 5Innovo Mimetics Ltd., Jerusalem, Israel.

6. 6Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv-Yafo, Israel.

7. 7Institute of Pathology, Sheba Medical Center, Ramat Gan, Israel.

Abstract

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 IFNγ-dependent, as it was abolished by β2M-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 IFNγ-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 CD8+ cell infiltration and clinical response. Silencing ADAR1-p150 abolished the IFNγ-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 IFNγ-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 IFNγ, which can drive T-cell infiltration.

Funder

Israel Science foundation

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Immunology

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