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

Abstract

The effect of tumor/T-cell interactions on subsequent immune infiltration is undefined. Here we report that pre-exposure 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 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, co-cultures 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-sequencing 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.

Clinical significance, tumor immune landscape and immunotherapy responses of ADAR in pan-cancer and its association with proliferation and metastasis of bladder cancer

“…One study showed that the deletion of PTPN2 phosphatase in T cells promotes antitumor immunity and CAR T-cell efficacy in solid tumors [ 33 ]. Another study demonstrated that ADAR promotes T-cell migration to human melanoma cells [ 34 ]. In addition, ADAR has been shown to improve Treg cell function via the miR-21b/Foxp3 axis [ 35 ].…”

Epigenetic regulation in the tumor microenvironment: molecular mechanisms and therapeutic targets

“…This positive feedback mechanism could have crucial effects on the growth of hot tumors as well as the great response to immunotherapy. 281 Antienzyme inhibitor 1(AZIN1) is one of the most prevalent Ato-I RNA-edited proteins in several human cancers. The functional effects of RNA-edited AZIN1 on tumor angiogenesis have been exhaustively studied recently.…”

“…This positive feedback mechanism could have crucial effects on the growth of hot tumors as well as the great response to immunotherapy. 281 …”

ADAR1 affects gastric cancer cell metastasis and reverses cisplatin resistance through AZIN1

“…ADAR1 has two subtypes of promoters, that is, the p110 and p150 subtypes, which have different roles in cancer development [ 4 ]. In melanoma, silencing the ADAR1-p150 subtype abolishes IFN-γ-driven T-cell migration, and silencing and overexpressing the ADAR1-p110 subtype reduces and increases T-cell migration, respectively [ 5 ]. ADAR1 regulates the peritoneal implantation and metastasis of gastric cancer cells through Wnt/β-catenin signaling in gastric cancer tissue [ 6 ].…”