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Depletion of RNA-editing enzyme ADAR1 invigorates NK cells anti-tumor immunity

ABSTRACT: Function exhaustion and inefficient tumor infiltration rate limit NK cells based cancer immunotherapy. Even though the role of ADAR1 in immune cells and tumorigenesis is gradually gaining attention, its role on NK cells is elusive. In this study, we found ADAR1 expression level was upregulated in peripheral blood (PB)-NK cells from patients with melanoma. ADAR1 knockdown NK cells showed enhanced anti-tumor activity in vitro and in vivo. NK cells specific Adar1 deletion mice showed better tumor control and higher NK cells infiltration level. RNA-seq analysis revealed that NK shADAR1 cells exhibited an activation phenotype with highly cell migration potential. Higher tumor infiltration level of NK shADAR1 cells were verified in three-dimensional (3D) Matrigel-spheroid experiment. Mechanically, we also observed ADAR1 deficiency in NK cells accompanied by RIG-I signaling pathway inhibition and CD38 expression decline, resulting in higher cell mobility, proliferation, and tumor killing capacity. These data suggest ADAR1 may be an emerging therapeutic target for enhanced NK cell immunotherapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE275892 | GEO | 2026/06/03

REPOSITORIES: GEO

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ADAR1 expression is associated with cervical cancer progression and negatively regulates NK cell activity

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2025-05-21 | GSE297095 | GEO

Loss of ADAR1 in tumor cells activates cDC1s and sensitizes pancreatic cancer to immunotherapy

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Nur77 agonism invigorates Natural Killer cell immunity against hepatocellular carcinoma [Spatial Transcriptomics]

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2026-05-19 | GSE320059 | GEO

ADAR1 regulates the resistance of melanoma cells to T cells via miR-222 and ICAM1

Project description:The blossom of immunotherapy in melanoma highlights the need to delineate mechanisms of immune resistance. Recently, we have demonstrated that the RNA editing protein, adenosine deaminase acting on RNA-1 (ADAR1) is down-regulated during metastatic transition of melanoma, which enhances melanoma cell proliferation and tumorigenicity. Here we investigate the role of ADAR1 in melanoma immune resistance. Importantly, knockdown of ADAR1 in human melanoma cells induces resistance to tumor infiltrating lymphocytes in a cell contact-dependent mechanism. We show that ADAR1, in an editing-independent manner, regulates the biogenesis of miR-222 at the transcription level and thereby Intercellular Adhesion Molecule 1 (ICAM1) expression, which consequently affects melanoma immune resistance. ADAR1 thus has a novel, pivotal, role in cancer immune resistance. Corroborating with these results, the expression of miR-222 in melanoma tissue specimens was significantly higher in patients who had no clinical benefit from treatment with ipilimumab as compared to patients that responded clinically, suggesting that miR-222 could function as a biomarker for the prediction of response to ipilimumab. These results provide not only novel insights on melanoma immune resistance, but also pave the way to the development of innovative personalized tools to enable optimal drug selection and treatment. 13 formalin fixed paraffin embedded (FFPE) melanoma tissues were stained with hematoxilin and eosin for examination by an expert pathologist. Non-tumor tissue was removed. Total RNA was isolated using miRNeasy FFPE kit (Qiagen) according to the manufacture guidelines.

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2024-10-18 | GSE241039 | GEO

Bone invigorates metastatic seeding [RNA-seq]

Project description:We herein examine the transciptioal alteration of a single cell derived MDA-MB-231 subline,SCP21. By retrieving tumor cells inoculated in different sites, we generated multiple mammary fat pad tumor, lung metastases or bone metastasis derived SCP21 sublines. RNA-sequencing uncovered the decreased expression of EZH2 target genes in bone metastases derived cells compared other organ entrained and parental SCP21 cells , suggesting enhanced EZH2 activity. Moreover, such phenotype is reversible upon in vitro culture. As a positive control, bone derived cells were also treated with EZH2 inhibitor, EPZ011989, to confirm the decreased level of EZH2 target genes upon EZH2 inhibition.

2021-04-29 | GSE160773 | GEO

All-trans retinoic acid destabilizes ADAR1 protein through retinoylation-mediated USP7 dissociation and improves immunotherapy in pancreatic cancer

Project description:ADAR1-p150 isoform, an interferon-stimulated double-stranded RNA-editing enzyme, contributes to immunotherapy resistance by suppressing interferon signaling. While genetic depletion of ADAR1 overcomes immunotherapy resistance in preclinical models, therapeutic targeting of ADAR1 has not been achieved to date in clinical setting. In this study, we found that the FDA-approved all-trans retinoic acid (ATRA) promoted ADAR1 protein degradation in different types of cancer. In addition, ATRA also induces the transcription of PD-L1 in cancer cells and the combination of ATRA and PD-1 blockade reprogrammed the tumor microenvironment to unleash antitumor immunity, thereby impeding tumor growth in vivo. Mechanistically, we identified deubiquitinase USP7 as a key regulator for ADAR1 protein stability. ATRA disrupts the USP7-ADAR1 interaction, promoting ADAR1 degradation. Notably, the regulation of ADAR1 protein degradation by ATRA is independent of its canonical receptors. Instead, ATRA treatment leads to ADAR1 retinoylation, a post-translational modification by conjugation of retinoids, which results in the disruption of USP7-ADAR1 complex to promote ADAR1polyubiquitination. Importantly, clinical data shows a positive correlation between USP7 and ADAR1 protein expression in various cancers, supporting USP7's role in ADAR1 stabilization. Overall, this study sheds light on the control of ADAR1 protein turnover and proposes a mechanism-driven combination therapy using ATRA and PD-1/PD-L1 blockade to convert immunologically cold into hot tumors, holding potential for clinical translation.

2025-07-19 | MSV000098564 | MassIVE

CXCL10-induced chemotaxis of ex vivo-expanded natural killer cells combined with NKTR-255 enhances anti-tumor efficacy in osteosarcoma

Project description:Osteosarcoma (OSA) has a dismal prognosis despite surgical resection and multiagent chemotherapy. While adoptive natural killer (NK) cell therapies have been successful in hematological malignancies, the application in solid tumors is challenging due to a tumor microenvironment (TME) that impairs NK cell tumor infiltration. Here, we found that ex vivo expansion of NK cells significantly increases the expression of C-X-C motif chemokine receptor 3 (CXCR3), one of the major proteins in the regulation of NK cell chemotaxis. Engineered over-secretion of CXCR3 ligands, C-X-C motif chemokine ligand (CXCL)9, -10, or -11, from OSA cells significantly enhanced expanded NK cell migration toward OSA cells in vitro and infiltration into the TME in vivo, with the highest NK infiltration rate in CXCL10-secreting tumors. Infusions of expanded NK cells significantly reduced (p = 0.02), and concomitant treatment with an interleukin (IL)-15 agonist NKTR-255 further reduced tumor burden and significantly increased survival in mice bearing CXCL10-secreting tumors compared with those with wild-type tumors (p = 0.02). Single-cell RNA sequencing and mass cytometry revealed upregulated apoptosis and transforming growth factor-β (TGF-β) signaling as the potential mechanisms of response/resistance to NK cell therapy in vivo. Our findings highlight potential application of chemokine-enhanced NK tumor infiltration in combination with an IL-15 agonist as a novel approach to effective treatment of OSA.

2025-06-10 | GSE297427 | GEO

RNF31 inhibition sensitizes tumors to bystander killing by innate and adaptive immune cells

Project description:Tumor escape mechanisms for immunotherapy include deficiencies in antigen presentation, diminishing adaptive CD8+ T cell antitumor activity. Although innate NK cells are triggered by loss of MHC class I, their response is often inadequate. To increase tumor susceptibility to both innate and adaptive immune elimination, we performed parallel genome-wide CRISPR-Cas9 screens. This identified all components, RNF31, RBCK1, and SHARPIN, of the linear ubiquitination chain assembly complex (LUBAC). Genetic and pharmacologic ablation of RNF31, an E3 ubiquitin ligase, strongly sensitized melanoma, breast and colorectal cancer cells to both NK and CD8+ T cell killing. This occurred in a TNF-dependent manner, causing loss of A20 and non-canonical IKK complexes from TNF Receptor Complex I. Corroborating this preclinically, a small molecule RNF31 inhibitor sensitized human colon carcinoma organoids to TNF and greatly enhanced immune bystander killing of antigen-loss and antigen presentation machinery-deficient tumor cells. These results merit exploration of RNF31 inhibition as a clinical pharmacological opportunity for immunotherapy-refractory cancers.

2022-05-30 | PXD029489 | Pride

Eubacterium rectale improves the efficacy of anti-PD1 immunotherapy in melanoma via L-serine-mediated NK-cell activation

Project description:NK cells, as a type of key immune cell, play essential roles in tumor cell immune escape and immunotherapy. Accumulating evidence has demonstrated that the gut microbiota community affects the efficacy of anti-PD1 immunotherapy and that remodeling the gut microbiota structure is a promising strategy to enhance anti-PD1 immunotherapy responsiveness in advanced melanoma patients; however, the details of the mechanism remain elusive. In this study, we found that Eubacterium rectale (E. rectale) was significantly enriched in melanoma patients who responded to anti-PD1 immunotherapy and a high E. rectale abundance was related to longer survival in melanoma patients. Furthermore, administration of E. rectale remarkably improved the efficacy of anti-PD1 therapy and benefited the overall survival of tumor-bearing mice; moreover, application of E. rectale significantly recruited NK cells into the tumor microenvironment. Interestingly, conditioned medium isolated from an E. rectale culture system dramatically enhanced NK-cell function. Through GC-MS/ UHPLC-MS/MS-based metabolomic analysis, L-serine production was found to be significantly decreased in the E. rectale group; moreover, administration of an L-serine synthesis inhibitor dramatically increased NK-cell activation, which led to enhanced anti-PD1 immunotherapy effects. Mechanistically, supplementation with L-serine or application of the L-serine synthesis inhibitor affected NK-cell activation through Fos/Fosl. In summary, our findings reveal the role of bacteria-modulated serine metabolic signaling in NK-cell activation and provide a novel therapeutic strategy to improve the efficacy of anti-PD1 immunotherapy in melanoma.

2023-04-14 | GSE225920 | GEO

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