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.
|Number of pages||14|
|Journal||Cancer Immunology Research|
|State||Published - Sep 2022|
Bibliographical noteFunding Information:
N. Margolis reports grants from Israel Science Foundation IPMP; and grants from Samueli Foundation during the conduct of the study. H. Moalem reports grants from Israel Science Foundation; and grants from Samueli Foundation during the conduct of the study. T. Meirson reports personal fees from TyrNovo outside the submitted work. B. Vizel reports grants from Israel Science Foundation; and grants from Samueli Foundation during the conduct of the study. M.J. Besser reports personal fees from KSQ Therapeutics, Gilboa Therapeutics, Sartorius; and personal fees from MSD outside the submitted work. G. Markel reports grants from Israel Science foundation; and grants from Samueli Foundation during the conduct of the study; personal fees from 4C Biomed, Starget, NucleAI, BeyondAir, MSD, Roche; grants and personal fees from BMS, Novartis; and grants and personal fees from Sanofi outside the submitted work. No disclosures were reported by the other authors.
G. Markel was supported by grant from Israel Science foundation (IPMP 3956) and grant for integrative immuno-oncology from the Samueli Foundation.
©2022 American Association for Cancer Research.