Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade

Ishizuka, Jeffrey J.; Manguso, Robert T.; Cheruiyot, Collins; Bi, Kevin; Panda, Arpit; Iracheta-Vellve, Arvin; Miller, Brian C.; Du, Peter; Yates, Kathleen B.; Dubrot, Juan; Buchumenski, Ilana; Comstock, Dawn E.; Brown, Flavian D.; Ayer, Austin; Kohnle, Ian C.; Pope, Hans W.; Zimmer, Margaret D.; Sen, Debattama R.; Lane-Reticker, Sarah Kate; Robitschek, Emily; Griffin, Gabriel K.; Collins, Natalie B.; Long, Adrienne H.; Doench, John G.; Kozono, David; Levanon, Erez Y.; Haining, W. Nicholas

doi:10.1038/s41586-018-0768-9

Cited by 517 publications

(468 citation statements)

References 41 publications

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“…Although the association with Type-I and Type-II interferons suggested immune activation in vivo, the ISGs IRF1 and IRF2 29 were not coinduced, indicative of suppressed downstream signaling and/or pathway inhibition. 33,39,40 Taken together, these data suggest that the presumably protective effects of RIG-I activation and interferon production become neutralized, and finally overridden, by checkpointdependent immunosuppression as well as infiltration with Tregs and direct pathway inhibition through EZH2. This observation suggests that in OC, RIG-I expression (but not necessarily activity) is uncoupled from negative EZH2-control.…”

Section: Discussionmentioning

confidence: 86%

“…25,27,38 Moreover, RIG-I levels in ovarian tumors were quite strongly associated with ADAR1 expression, an immune-silencing factor that may reduce the sensitivity to checkpoint inhibition. 33,39,40 Taken together, these data suggest that the presumably protective effects of RIG-I activation and interferon production become neutralized, and finally overridden, by checkpointdependent immunosuppression as well as infiltration with Tregs and direct pathway inhibition through EZH2. The concerted action of these nonredundant mechanisms may abolish tumor immune surveillance, thus fostering tumor growth and imposing a poor outcome.…”

Section: Discussionmentioning

confidence: 86%

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High RIG‐I expression in ovarian cancer associates with an immune‐escape signature and poor clinical outcome

Wolf

Fiegl

Zeimet

et al. 2019

Intl Journal of Cancer

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Ovarian cancer (OC) is the most lethal gynecological malignancy, with platinum‐based chemotherapy remaining the mainstay for adjuvant treatment after surgery. The lack of indication for immunotherapy may at least in part result from the lack of suitable biomarkers allowing stratification of potentially responding patients. In this monocentric study of 141 cases with OC, we used real‐time quantitative PCR to assess the expression of retinoic acid‐inducible gene‐I (RIG‐I) in primary tumor and healthy ovarian control tissues. RIG‐I expression was correlated to various clinicopathological characteristics as well as to a set of molecular and immunological markers. The prognostic significance of RIG‐I expression was queried in univariate and multivariate analyses and validated in an independent cohort. RIG‐I was overexpressed in the cancerous ovary and correlated with a higher tumor grade. The more aggressive Type‐II cancers and cancers with inactivating p53 mutations exhibited higher RIG‐I expression. RIG‐I levels were also elevated in cancers that recurred after remission or were platinum‐refractory. Survival analyses disclosed RIG‐I as an independent marker of poor outcome in OC. Continuative analyses revealed the molecular and immunological correlates of RIG‐I expression in the tumor microenvironment, including interferon production and a distinct immune‐regulatory signature involving checkpoint molecules (PD‐L1/PD‐1), the RNA‐editing enzyme ADAR1 and the regulatory T cell‐specific transcription factor FoxP3. We conclude that high RIG‐I expression associates with poor outcome in OC, which is explainable by local immunosuppression in the tumor bed. RIG‐I expression may inform checkpoint blockade and/or RIG‐I agonistic targeting in a subset of high‐risk OC patients.

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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 86%

High RIG‐I expression in ovarian cancer associates with an immune‐escape signature and poor clinical outcome

Wolf

Fiegl

Zeimet

et al. 2019

Intl Journal of Cancer

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“…ADAR1 is thought to inactivate an excess of dsRNA, which further stimulates cell immunity. Thus, this isoform participates in immune suppressing pathways which may facilitate cancer growth . While ADAR1 reacts with long stretches of dsRNA, the ADAR2, in a yet unknown manner, specifically modifies selected residues in coding regions of mRNAs.…”

Section: Introductionmentioning

confidence: 99%

Adenosine‐to‐Inosine RNA Editing in Mouse and Human Brain Proteomes

et al. 2019

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Proteogenomics is based on the use of customized genome or RNA sequencing databases for interrogation of shotgun proteomics data in search for proteome‐level evidence of genome variations or RNA editing. In this work, the products of adenosine‐to‐inosine RNA editing in human and murine brain proteomes are identified using publicly available brain proteome LC‐MS/MS datasets and an RNA editome database compiled from several sources. After filtering of false‐positive results, 20 and 37 sites of editing in proteins belonging to 14 and 32 genes are identified for murine and human brain proteomes, respectively. Eight sites of editing identified with high spectral counts overlapped between human and mouse brain samples. Some of these sites have been previously reported using orthogonal methods, such as α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) glutamate receptors, CYFIP2, coatomer alpha. Also, differential editing between neurons and microglia is demonstrated in this work for some of the proteins from primary murine brain cell cultures. Because many edited sites are still not characterized functionally at the protein level, the results provide a necessary background for their further analysis in normal and diseased cells and tissues using targeted proteomic approaches.

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“…ADAR1 regulates the biogenesis of members of the miR-222 family and thereby ICAM1 expression, which ultimately leads to immune resistance [60]. Loss of function of ADAR1 in tumor cells strongly sensitizes tumors to immunotherapy and overcomes resistance to PD1 checkpoint blockade [61]. Surprisingly, in this study, blocking ADAR1 function with EHNA drug did not result in breaking resistance of HPAFII and CFPAC cells to CAR T cells treatment.…”

Section: Discussionmentioning

confidence: 51%

Overcoming Immunological Resistance Enhances the Efficacy of a Novel anti-tMUC1 CAR T Cell Treatment Against Pancreatic Ductal Adenocarcinoma

Yazdanifar

Zhou

Grover

et al. 2019

Preprint

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Chimeric antigen receptor engineered T cells (CAR T cells) have shown remarkable success in treating hematologic cancers. However, this efficacy has yet to translate to treatment in solid tumors. Pancreatic ductal adenocarcinoma (PDA) is a fatal malignancy with poor prognosis. Treatment options are limited and commonly associated with severe side effects. We have developed and characterized a second generation CAR engineered T cell using the light and heavy chain sequence derived from a novel monoclonal antibody, TAB004, that specifically binds the tumor associated antigen, tMUC1. tMUC1 is overexpressed in varying levels on ~85% of all human PDA. We present data showing that the TAB004 derived CAR T cells (tMUC1-CAR T cells) specifically bind to tMUC1 on PDA cells and is cytotoxic against the majority of the PDA cell lines. The tMUC1-CAR T cells do not bind or kill normal epithelial cells. We further demonstrate that the tMUC1-CAR T cells control the growth of orthotopic pancreatic tumors in vivo. PDAs are generally cold tumors with resistance to many standard treatment modalities, thus, it was not surprising that some of the PDA cell lines were refractory to CAR T cell treatment. qPCR analysis of several genes known to be associated with immune resistance revealed overexpression of indoleamine 2, 3-dioxygenases-1 (IDO1), Cyclooxygenase 1 and 2 (COX1 and COX2), Adenosine deaminases acting on RNA (ADAR1) and galectin-9 (Gal-9). We treated resistant PDA cells with a combination of CAR T cells and biological inhibitors of IDO1, COX1/2, ADAR1, and Gal-9. Results showed a significant enhancement of CAR T cell cytotoxicity against PDA cells when inhibiting IDO1, COX1/2, and Gal-9 but not ADAR1 or COX2. Overcoming CAR T cell resistance in PDA is a significant advancement in the field and may lead to future combination therapies that are less toxic but more efficient against this deadly disease. ductal adenocarcinoma (PDA), pancreatic cancer, and tumor associated MUC1 (tMUC1). T cell cytotoxicityTo test T cell cytotoxicity against target cells, 5,000-10,000 cancer cells or normal cells were plated in triplicate in 96 well plates one day prior to co-culture. Mock or CAR T cells were counted and added to cancer cells at the indicated target to effector (T:E) ratio. Cell viability was evaluated by MTT assay (MTT 500 ug/ml, Sigma) 24, 48, and 72 hrs after co-culture according to the product instructions. The OD value at 540 nm was read and percentage survival was calculated as 100-[(mock T OD -CAR T OD)/mock T OD Apoptosis assayMock and CAR T cells were stained with Annexin V/propidium iodide (PI) dyes according to the Dead Cell Apoptosis Kit protocol (Life Technology V13242) before and after co-culture with cancer cells for 24, 48, and 72 hrs. The percentage of positive cells was assessed using flowcytometry.

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Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade

Cited by 517 publications

References 41 publications

High RIG‐I expression in ovarian cancer associates with an immune‐escape signature and poor clinical outcome

High RIG‐I expression in ovarian cancer associates with an immune‐escape signature and poor clinical outcome

Adenosine‐to‐Inosine RNA Editing in Mouse and Human Brain Proteomes

Overcoming Immunological Resistance Enhances the Efficacy of a Novel anti-tMUC1 CAR T Cell Treatment Against Pancreatic Ductal Adenocarcinoma

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