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

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 ß2M-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.

Reprogramming lymphocytes for the treatment of melanoma: From biology to therapy.

This decade has introduced drastic changes in melanoma therapy, predominantly due to the materialization of the long promise of immunotherapy. Cytotoxic T cells are the chief component of the immune system, which are targeted by different strategies aimed to increase their capacity against melanoma cells. To this end, reprogramming of T cells occurs by T cell centered manipulation, targeting the immunosuppressive tumor microenvironment or altering the whole patient. These are enabled by delivery of small molecules, functional monoclonal antibodies, different subunit vaccines, as well as living lymphocytes, native or genetically engineered. Current FDA-approved therapies are focused on direct T cell manipulation, such as immune checkpoint inhibitors blocking CTLA-4 and/or PD-1, which paves the way for an effective immunotherapy backbone available for combination with other modalities. Here we review the biology and clinical developments that enable melanoma immunotherapy today and in the future.