Clonal multi-omics reveals Bcor as a negative regulator of emergency dendritic cell development

Tian, Luyi; Tomei, Sara; Schreuder, Jaring; Weber, Tom S.; Amann‐Zalcenstein, Daniela; Lin, Dawn; Tran, Jessica; Audiger, Cindy; Chu, Mathew; Jarratt, Andrew; Willson, Tracy A.; Hilton, Adrienne; Pang, Ee Shan; Patton, Timothy; Kelly, Madison J.; Su, Shian; Gouil, Quentin; Diakumis, Peter; Bahlo, Melanie; Sargeant, Tobias; Kats, Lev; Hodgkin, Philip D.; O’Keeffe, Meredith; Ng, Ashley P.; Ritchie, Matthew E.; Naik, Shalin H.

doi:10.1016/j.immuni.2021.03.012

Cited by 33 publications

(35 citation statements)

References 78 publications

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“…One had similar molecular characteristics with patients with EBVnGC, such as TP53 mutation (c.844C>T), while the other had a deleterious BCOR mutation, which might account for the poor benefit from ICB for that BCOR deletion had been documented to perturb dendritic cell development. 35 These phenomena might be reminiscent of the EBV status detected by NGS with high accuracy of ICB efficacy prediction and potential false positivity of EBV identification by EBER-ISH. Given the challenge of false-positive/false-negative EBER-ISH results, incorporating NGS-based methods may improve the diagnostic accuracy of EBV-related diseases and better inform follow-up treatment.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and predictive biomarkers of immunotherapy in Epstein-Barr virus-associated gastric cancer

Bai

Xie

Wang

et al. 2022

J Immunother Cancer

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BackgroundEpstein-Barr virus (EBV)-associated gastric cancer (GC) (EBVaGC) is a distinct molecular subtype of GC with a favorable prognosis. However, the exact effects and potential mechanisms of EBV infection on immune checkpoint blockade (ICB) efficacy in GC remain to be clarified. Additionally, EBV-encoded RNA (EBER) in situ hybridization (ISH), the traditional method to detect EBV, could cause false-positive/false-negative results and not allow for characterizing other molecular biomarkers recommended by standard treatment guidelines for GC. Herein, we sought to investigate the efficacy and potential biomarkers of ICB in EBVaGC identified by next-generation sequencing (NGS).DesignAn NGS-based algorithm for detecting EBV was established and validated using two independent GC cohorts (124 in the training cohort and 76 in the validation cohort). The value of EBV infection for predicting ICB efficacy was evaluated among 95 patients with advanced or metastatic GC receiving ICB. The molecular predictive biomarkers for ICB efficacy were identified to improve the prediction accuracy of ICB efficacy in 22 patients with EBVaGC.ResultsCompared with orthogonal assay (EBER-ISH) results, the NGS-based algorithm achieved high performance with a sensitivity of 95.7% (22/23) and a specificity of 100% (53/53). EBV status was identified as an independent predictive factor for overall survival and progression-free survival in patients with DNA mismatch repair proficient (pMMR) GC following ICB. Moreover, the patients with EBV+/pMMR and EBV−/MMR deficient (dMMR) had comparable and favorable survival following ICB. Twenty-two patients with EBV+/pMMR achieved an objective response rate of 54.5% (12/22) on immunotherapy. Patients with EBVaGC with a high cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) level were less responsive to anti-programmed death-1/ligand 1 (PD-1/L1) monotherapy, and the combination of anti-CTLA-4 plus anti-PD-1/L1 checkpoint blockade benefited patients with EBVaGC more than anti-PD-1/L1 monotherapy with a trend close to significance (p=0.074). There were nearly significant differences in tumor mutational burden (TMB) level and SMARCA4 mutation frequency between the ICB response and non-response group.ConclusionsWe developed an efficient NGS-based EBV detection strategy, and this strategy-identified EBV infection was as effective as dMMR in predicting ICB efficacy in GC. Additionally, we identified CTLA-4, TMB, and SMARCA4 mutation as potential predictive biomarkers of ICB efficacy in EBVaGC, which might better inform ICB treatment for EBVaGC.

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Section: Discussionmentioning

confidence: 99%

Efficacy and predictive biomarkers of immunotherapy in Epstein-Barr virus-associated gastric cancer

Bai

Xie

Wang

et al. 2022

J Immunother Cancer

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“…The latter effect is not consistent with the proposed role of E2A in pDC development (Bagadia et al, 2019) and requires further study. Notably, the top gene with high score specifically in DCs was Bcor , encoding a transcriptional corepressor that was recently identified as a negative regulator of Flt3L-driven DC differentiation (Tian et al, 2021). The enrichment of these genes was detectable in cDC2s but less pronounced in pDCs (Fig.…”

Section: Resultsmentioning

confidence: 99%

Genome-wide analysis of dendritic cell differentiation

Tiniakou

Hsu

Lopez-Zepeda

et al. 2022

Preprint

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SummaryDendritic cells (DCs) are immune sentinel cells that comprise antigen-presenting conventional DCs (cDCs) and cytokine-producing plasmacytoid DCs (pDCs). Cytokine Flt3 ligand (Flt3L) supports the proliferation of hematopoietic progenitors, and is also necessary and sufficient for DC differentiation. Here we characterized the spontaneous differentiation of a Flt3L-dependent murine progenitor cell line into pDCs and “myeloid” cDCs (cDC2s), and interrogated it using a genome-wide CRISPR/Cas9 dropout screen. The screen revealed multiple regulators of DC differentiation including the glycosylphosphatidylinositol transamidase complex, the Nieman-Pick type C cholesterol transporter and arginine methyltransferase Carm1; the role of Carm1 in pDC and cDC2 differentiation was confirmed by conditional targeting in vivo. We also found that negative regulators of mTOR signaling, including the subunits of TSC and GATOR1 complexes, restricted progenitor growth but enabled DC differentiation. The results provide a comprehensive forward genetic analysis of DC differentiation, and help explain how the opposing processes of proliferation and differentiation could be driven by the same cytokine.

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“…This would allow one to determine clone behaviors and lineage connections over repeated amputations which should, in principle, allow one to determine if clone behaviors are heritable or are largely the product of location and proximity to extrinsic cues for migration, proliferation, and so forth. 45,46,50,51 The limb regeneration model is a challenging yet ideal in vivo model to query the heterogeneity of lineage decisions during morphogenesis. There are some recent insights into the role of kinetics of blastema cell recruitment on the contribution of cells to the regenerate.…”

Section: How Do Cell Behaviors and Lineage Decisions Influence Limb R...mentioning

confidence: 99%

“…Another extension of barcoded or clonally labeled tissue would be to sample a single limb prior to and during repeated rounds of regeneration. This would allow one to determine clone behaviors and lineage connections over repeated amputations which should, in principle, allow one to determine if clone behaviors are heritable or are largely the product of location and proximity to extrinsic cues for migration, proliferation, and so forth 45,46,50,51 . The limb regeneration model is a challenging yet ideal in vivo model to query the heterogeneity of lineage decisions during morphogenesis.…”

Section: How Do Cell Behaviors and Lineage Decisions Influence Limb R...mentioning

confidence: 99%

Rebuilding limbs, one cell at a time

Leigh

Currie

2022

Developmental Dynamics

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Clonal multi-omics reveals Bcor as a negative regulator of emergency dendritic cell development

Cited by 33 publications

References 78 publications

Efficacy and predictive biomarkers of immunotherapy in Epstein-Barr virus-associated gastric cancer

Efficacy and predictive biomarkers of immunotherapy in Epstein-Barr virus-associated gastric cancer

Genome-wide analysis of dendritic cell differentiation

Rebuilding limbs, one cell at a time

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