Tumor mutational burden is a determinant of immune-mediated survival in breast cancer

Thomas, Alexandra; Routh, Eric D.; Pullikuth, Ashok; Jin, Guangxu; Su, Jing; Chou, Jeff W.; Hoadley, Katherine A.; Print, Cristin G.; Knowlton, Nicholas; Black, Michael A.; Demaria, Sandra; Wang, Ena; Bedognetti, Davide; Jones, Wendell; Mehta, Gaurav; Gatza, Michael L.; Perou, Charles M.; Page, David B.; Triozzi, Pierre L.; Miller, Lance D.

doi:10.1080/2162402x.2018.1490854

Cited by 221 publications

(235 citation statements)

References 58 publications

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“…To test the applicability of the study-derived immune signatures in other cancers, we probed TCGA RNA-Seq data for uterine corpus endometrial cancer (UCEC) and high tumor mutational burden (Hi-TMB) breast cancer (BRCA) patients [24,25]. The patient characteristics for these two cohorts are shown in Table S4.…”

Section: Significance Of Pan-cancer-based Immune Signature In Other Cmentioning

confidence: 99%

RNA Immune Signatures from Pan-Cancer Analysis Are Prognostic for High-Grade Serous Ovarian Cancer and Other Female Cancers

Jones

Michener

Biscotti

et al. 2020

Cancers

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Immune cell infiltrates within the tumor microenvironment can influence treatment response and outcome in several cancers. In this study, we developed RNA-based immune signatures from pan-cancer analysis that could serve as potential markers across tumor types and tested them for association with outcome in high-grade serous ovarian cancer (HGSOC) and other female cancers. Pan-cancer RNA-Seq cluster analysis of immune-related gene expression profiles in The Cancer Genome Atlas (TCGA) from 29 different solid tumors (4446 specimens) identified distinct but concordant gene signatures. Among these immune signatures, Cytotoxic Lymphocyte Immune Signature (CLIS), T-cell trafficking (TCT), and the TCT to M2 tumor-associated macrophage (M2TAM) ratio (TCT:M2TAM) were significantly (p < 0.05) associated with overall survival (OS), using multivariable Cox proportional hazards regression models, in a discovery cohort and two independent validation cohorts of HGSOC patients. Notably, the TCT:M2TAM ratio was highly significant (p ≤ 0.000001) in two HGSOC cohorts. Immune signatures were also significant (p < 0.05) in the presence of tumor cytoreduction, BRCA1/2 mutation, and COL2A1 expression. Importantly, the CLIS and TCT signatures were also validated for prognostic significance (p < 0.05) in TCGA cohorts for endometrial and high tumor mutational burden (Hi-TMB) breast cancer. These immune signatures also have the potential for being predictive in other cancers and for patients following different treatment strategies.Cancers 2020, 12, 620 2 of 12 TME. Studies of the molecular mechanisms involved in immune surveillance within tumors has led to development of promising immunotherapies that have benefited a subset of patients. Furthermore, the immune landscape can also influence response to chemotherapy.High-grade serous ovarian cancer (HGSOC), the most common subtype of epithelial ovarian cancer (EOC), is usually diagnosed at an advanced stage [1]. Although most patients respond to initial adjuvant platinum/taxane-based chemotherapy, the rate of recurrence is relatively high [1,2]. Several clinical, genomic, and immune factors have been correlated with long-term survival, including age, stage, tumor grade, optimal or sub-optimal primary cytoreductive surgery, homologous-recombination deficiency (HRD), BRCA1/BRCA2 mutations, and the presence of intra-tumoral immune cells [3][4][5][6][7][8][9][10]. Patients with high levels of CD8 + tumor infiltrating lymphocytes, as assessed by immunohistochemistry [11][12][13], and patients with high ratios of M1 macrophage cells to M2 tumor-associated macrophage (M2TAM) cells in the TME [14] exhibit improved survival. Further, CXCR3, and its corresponding ligands (CXCL9, CXCL10, and CXCL11), which are frequently expressed by M1 macrophage and other cells in the TME and play a major role in T cell trafficking [15][16][17][18][19][20], are also associated with overall survival (OS) in EOC [21,22].The relationship between immune status determined by gene expression-based biomarkers, treatment re...

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Section: Significance Of Pan-cancer-based Immune Signature In Other Cmentioning

confidence: 99%

RNA Immune Signatures from Pan-Cancer Analysis Are Prognostic for High-Grade Serous Ovarian Cancer and Other Female Cancers

Jones

Michener

Biscotti

et al. 2020

Cancers

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“…In BRCA-1/2 mutated ovarian cancers, TMB correlates with improved overall survival [30,31]. In breast cancer patients, tumors with high TMB and favorable immune-infiltrate ("hot tumors") are associated with prolonged survival [32]. Consistently, basal cell carcinoma, which is characterized by very high TMB, presents with slow growth rates and rare metastases.…”

mentioning

confidence: 99%

Tumor mutational burden quantification from targeted gene panels: major advancements and challenges

Fancello

Gandini

Pelicci

et al. 2019

j. immunotherapy cancer

274

233

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Tumor mutational burden (TMB), the total number of somatic coding mutations in a tumor, is emerging as a promising biomarker for immunotherapy response in cancer patients. TMB can be quantitated by a number of NGS-based sequencing technologies. Whole Exome Sequencing (WES) allows comprehensive measurement of TMB and is considered the gold standard. However, to date WES remains confined to research settings, due to high cost of the large genomic space sequenced. In the clinical setting, instead, targeted enrichment panels (gene panels) of various genomic sizes are emerging as the routine technology for TMB assessment. This stimulated the development of various methods for panel-based TMB quantification, and prompted the multiplication of studies assessing whether TMB can be confidently estimated from the smaller genomic space sampled by gene panels. In this review, we inventory the collection of available gene panels tested for this purpose, illustrating their technical specifications and describing their accuracy and clinical value in TMB assessment. Moreover, we highlight how various experimental, platform-related or methodological variables, as well as bioinformatic pipelines, influence panel-based TMB quantification. The lack of harmonization in panel-based TMB quantification, of adequate methods to convert TMB estimates across different panels and of robust predictive cutoffs, currently represents one of the main limitations to adopt TMB as a biomarker in clinical practice. This overview on the heterogeneous landscape of panel-based TMB quantification aims at providing a context to discuss common standards and illustrates the strong need of further validation and consolidation studies for the clinical interpretation of panel-based TMB values. Electronic supplementary material The online version of this article (10.1186/s40425-019-0647-4) contains supplementary material, which is available to authorized users.

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“…Many previous studies have shown that EMT-related pathways and transcription factors are involved in the regulation of PD-L1. 23,24 It has been reported that ZEB1 can increase PD-L1 expression by activating miRNA-200 in NSCLC and results in a dysfunction of CD8+ T cells, which couples with epithelial-mesenchymal transition (EMT) to increase metastasis. In autochthonous mouse melanoma models, Spranger S. et al demonstrated that tumorintrinsic active β-catenin signaling results in T cell exclusion and resistance to anti-PD-L1/anti-CTLA-4 monoclonal antibody therapy.…”

Section: Discussionmentioning

confidence: 99%

PD-L1 regulation by SDH5 via β-catenin/ZEB1 signaling

Tuo

Zong

et al. 2019

OncoImmunology

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Programmed death-ligand 1 (PD-L1) is a crucial target for lung cancer immunotherapy. In lung cancer patients with high PD-L1 expression, blocking or reducing its expression can inhibit tumor growth. PD-L1 is regulated by signaling pathways, transcription factors and epigenetic factors, such as the GSK3β/β-catenin pathway, P53 protein and EMT. In our previous study, succinate dehydrogenase 5 (SDH5) was reported to regulate ZEB1 expression, induce EMT and lead to lung cancer metastasis via the GSK3β/β-catenin pathway. It is possible that SDH5 is involved in the mechanisms of PD-L1 regulation.In the present study, we observed a negative correlation between the expression of PD-L1 and SDH5 in vivo and in vitro. The examination of patient tissues also confirmed our results. Furthermore, we also found that SDH5 could reverse PD-L1 expression by the GSK3β/β-catenin/ZEB1 pathways. All these results reveal that SDH5 regulates PD-L1 expression and suggest that SDH5 can be used as a marker to predict tumor immune micro-states and provide guidance for clinical immunotherapy.

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Tumor mutational burden is a determinant of immune-mediated survival in breast cancer

Cited by 221 publications

References 58 publications

RNA Immune Signatures from Pan-Cancer Analysis Are Prognostic for High-Grade Serous Ovarian Cancer and Other Female Cancers

RNA Immune Signatures from Pan-Cancer Analysis Are Prognostic for High-Grade Serous Ovarian Cancer and Other Female Cancers

Tumor mutational burden quantification from targeted gene panels: major advancements and challenges

PD-L1 regulation by SDH5 via β-catenin/ZEB1 signaling

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