Augmenting Immunotherapy Impact by Lowering Tumor TNF Cytotoxicity Threshold

Vredevoogd, David W.; Kuilman, Thomas; Ligtenberg, Maarten A.; Boshuizen, Julia; Stecker, Kelly E.; Bruijn, Beaunelle de; Krijgsman, Oscar; Huang, Xinyao; Kenski, Juliana C.N.; Lacroix, Ruben; Mezzadra, Riccardo; Gomez-Eerland, Raquel; Yıldız, Mete; Dagidir, Ilknur; Apriamashvili, Georgi; Zandhuis, Nordin; Noort, Vincent van der; Visser, Nils L.; Blank, Christian U.; Altelaar, Maarten; Schumacher, Ton N.; Peeper, Daniel S.

doi:10.1016/j.cell.2020.01.005

Cited by 32 publications

(24 citation statements)

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“…Tumor immunology has emerged as a new field which has come of age in the last two decades (10). Tumor immunology contains immune parameters which can provide insights to prognostic predictions and immunotherapeutic strategies in cancers (23,24), so it is reasonable to revise the current cancer classification system to include these parameters (7,10). As one of the immune parameters, TIICs reveal the status of the tumor microenvironment (10).…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of the Immune Microenvironment Contributes to Malignant Progression and Has Prognostic Value in Bladder Cancer

et al. 2020

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ObjectiveThe malignant progression from non-muscle-invasive bladder cancer (NMIBC) to muscle-invasive bladder cancer (MIBC) is common and has detrimental effect on patients. We aimed to elucidate the underlying mechanisms of the malignant progression from an immunological perspective and establish a reliable signature for prognostic prediction and immunotherapeutic strategies.MethodsThe Cell Type Identification by Estimating Relative Subsets of RNA Transcripts algorithm was applied to the GSE32894 data set to identify the different tumor-infiltrating immune cells involved in NMIBC and MIBC. Using weighted gene correlation network analysis, survival analysis and least absolute shrinkage and selection operator Cox analysis, we established an immune prognostic signature (IPS) based on 14 overall survival-associated immune genes in The Cancer Genome Atlas (TCGA). Functional enrichment analyses and nomogram were performed to explore the potential effects and prognostic performance of the IPS. Furthermore, the RNA-sequence data from our center were used to validate the expression levels of the selected immune genes in BLCA samples.ResultsDiverse proportions of macrophage subtypes were observed between NMIBC and MIBC. Patients with high risk scores had a worse prognosis than patients with low risk scores in training (TCGA) and validation data sets (GSE32894, GSE13507, and GSE48277). The IPS was a useful prognostic factor for patients treated with immunotherapy in the IMvigor210 trial. Hallmarks of multiple oncogenic pathways were significantly enriched in the high risk group. A novel nomogram model was established for prognostic predictions. The dysregulated expression of the selected immune genes between NMIBC and MIBC was also validated in BLCA samples.ConclusionDysregulation of the immune microenvironment promoted the malignant progression from NMIBC to MIBC. The IPS can stratify patients into different risk groups with distinct prognoses and immunotherapeutic susceptibility, thus facilitating personalized immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Dysregulation of the Immune Microenvironment Contributes to Malignant Progression and Has Prognostic Value in Bladder Cancer

et al. 2020

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“…Remarkably, TRAF2 has been independently identi ed in recent functional work by Vredevoogd et al (Cell, 2018) (19) as the top hit in a genome wide CRISPR screen, for genes which when knocked out sensitize tumor cells to T cell-mediated elimination. Mechanistically, TRAF2 loss was shown to enhance CPI e cacy by lowering the tumor necrosis factor (TNF) cytotoxicity threshold and increasing T cell-mediated tumor cell apoptosis (19). The high frequency of 9q34.3 (TRAF2) loss in CPI responding tumors (44.1%), raises the prospect of identi cation of a novel and reasonably sized group of patients suitable for CPI.…”

Section: Loss Of 9q343 Sensitizes Tumors To Cpi Responsementioning

confidence: 99%

Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition

Litchfield

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et al. 2021

Cell

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Summary Checkpoint inhibitors (CPIs) augment adaptive immunity. Systematic pan-tumor analyses may reveal the relative importance of tumor-cell-intrinsic and microenvironmental features underpinning CPI sensitization. Here, we collated whole-exome and transcriptomic data for >1,000 CPI-treated patients across seven tumor types, utilizing standardized bioinformatics workflows and clinical outcome criteria to validate multivariable predictors of CPI sensitization. Clonal tumor mutation burden (TMB) was the strongest predictor of CPI response, followed by total TMB and CXCL9 expression. Subclonal TMB, somatic copy alteration burden, and histocompatibility leukocyte antigen (HLA) evolutionary divergence failed to attain pan-cancer significance. Dinucleotide variants were identified as a source of immunogenic epitopes associated with radical amino acid substitutions and enhanced peptide hydrophobicity/immunogenicity. Copy-number analysis revealed two additional determinants of CPI outcome supported by prior functional evidence: 9q34 ( TRAF2 ) loss associated with response and CCND1 amplification associated with resistance. Finally, single-cell RNA sequencing (RNA-seq) of clonal neoantigen-reactive CD8 tumor-infiltrating lymphocytes (TILs), combined with bulk RNA-seq analysis of CPI-responding tumors, identified CCR5 and CXCL13 as T-cell-intrinsic markers of CPI sensitivity.

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“…Upregulation of additional immune checkpoints such as TIM3, LAG3, and VISTA can be found at the time of acquired resistance, and may reflect terminal exhaustion and fixed loss of effector function. Vredevoogd et al (2019) also performed a genome-wide CRISPR/Cas9 screen of IFN-g receptor-deficient melanoma to identify IFN-g-independent pathways involved in anti-tumor immunity. In doing so, they uncovered that tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) inactivation within the TNF signaling pathway contributes to T cell elimination.…”

Section: Insights From New Toolsmentioning

confidence: 99%

Acquired Resistance to Immune Checkpoint Inhibitors

2020

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Immune checkpoint inhibitors (ICIs) have rapidly altered the treatment landscape for multiple tumor types, providing unprecedented survival in some patients. Despite the characteristic durability of response to ICI, unfortunately many patients with initial response will later develop acquired resistance. The current understanding of mechanisms of acquired resistance to ICIs is remarkably limited, perhaps restraining effective development of next-generation immunotherapies. Here, we examine the barriers to progress and emerging clinical reports interrogating acquired resistance with the goal to facilitate efforts to overcome acquired resistance to ICIs in the future.

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Augmenting Immunotherapy Impact by Lowering Tumor TNF Cytotoxicity Threshold

Cited by 32 publications

References 0 publications

Dysregulation of the Immune Microenvironment Contributes to Malignant Progression and Has Prognostic Value in Bladder Cancer

Dysregulation of the Immune Microenvironment Contributes to Malignant Progression and Has Prognostic Value in Bladder Cancer

Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition

Acquired Resistance to Immune Checkpoint Inhibitors

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