Fibroblast growth factor receptor 3 alterations and response to immune checkpoint inhibition in metastatic urothelial cancer: a real world experience

Rose, Tracy L.; Weir, William H.; Mayhew, Gregory M.; Shibata, Yoichiro; Eulitt, Patrick; Uronis, Joshua M.; Zhou, Mi; Nielsen, Matthew E.; Smith, Angela; Woods, Michael; Hayward, Michele C.; Salazar, Ashley H.; Milowsky, Matthew I.; Wobker, Sara E.; McGinty, Katrina; Millburn, Michael V.; Eisner, Joel R.; Kim, William Y.

doi:10.1038/s41416-021-01488-6

Cited by 95 publications

(94 citation statements)

References 41 publications

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“…To investigate the predictive efficacy of PRGScore on patient response to immunotherapy, we included processed gene expression of a metastatic urothelial cancer (mUC) cohort (EGAS00001002556) that received atezolizumab treatment via the R package IMvigor210CoreBiologies ( ) ( 14 ). In addition, we obtained a mUC cohort (GSE176307) ( 38 ) that received immune checkpoint blockade (ICB) from GEO. We also obtained processed RNA-seq data in a transcripts per million (TPM) matrix of patients treated with anti-PD1 ICB from a large melanoma genome sequencing project (MGSP) ( 39 ).…”

Section: Methodsmentioning

confidence: 99%

Pyroptosis-Related Signature Predicts Prognosis and Immunotherapy Efficacy in Muscle-Invasive Bladder Cancer

et al. 2022

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Pyroptosis has profound impacts on tumor cell proliferation, invasion, and metastasis and is of great clinical significance for different cancers. However, the role of pyroptosis in the progression and prognosis of muscle invasive bladder cancer (MIBC) remains poorly characterized. Here, we collected multicenter MIBC data and performed integrated analysis to dissect the role of pyroptosis in MIBC and provide an optimized treatment for this disease. Based on transcriptomic data, we developed a novel prognostic model named the pyroptosis-related gene score (PRGScore), which summarizes immunological features, genomic alterations, and clinical characteristics associated with the pyroptosis phenotype. Samples with high PRGScore showed enhancement in CD8+ T cell effector function, antigen processing machinery and immune checkpoint and better response to immunotherapy by programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors, which indicates that PRGScore is a valuable signature in the identification of populations sensitive to immune checkpoint inhibitors. Collectively, our study provides insights into further research targeting pyroptosis and its tumor immune microenvironment (TME) and offers an opportunity to optimize the treatment of MIBC.

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Section: Methodsmentioning

confidence: 99%

Pyroptosis-Related Signature Predicts Prognosis and Immunotherapy Efficacy in Muscle-Invasive Bladder Cancer

et al. 2022

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“…12 Immune checkpoint blockade immunotherapeutic (ICB) cohorts with FPKM or CPM transcriptomic were collected from the public database, included 8 melanoma datasets (Ulloa et al (2013, MAGE A3,Melanoma [ 22 ]);Gide et al (2019, anti-PD1 or anti-PD1 + CTLA4, Melanoma [ 23 ]); Nathanson (2017 CTLA4, Melanoma [ 24 ]); Hugo et al (2016, anti-PD1, Met Melanoma [ 25 ]); Lauss et al (2017, ACT, Melanoma [ 26 ]); Liu et al (2019, anti-PD1, Met Melanoma [ 27 ]); Riaz et al (2017, anti-PD1, Melanoma [ 28 ]); VanAllen (2016, CTLA4, MetMelanoma [ 29 ])), and other 4 non-melanoma cohorts (IMvigor210 (2018, anti-PDL1,Urothelial Cancer [ 30 ]); Braun et al (2020, anti-PD1, CCRCC [ 31 ]); JaeWon et al (2020, anti-PD1, NSCLC [ 32 ]);and Rose et al (2021, ICB, Bladder Cancer [ 33 ])). All patients had the immune response in these cohorts.…”

Section: Methodsmentioning

confidence: 99%

Single-cell N6-methyladenosine regulator patterns guide intercellular communication of tumor microenvironment that contribute to colorectal cancer progression and immunotherapy

et al. 2022

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Background N6-methyladenosine (m6A) RNA methylation plays a critical role in key genetic events for various cancers; yet, how m6A functions within the tumor microenvironment (TME) remains to be elucidated. Methods A total of 65,362 single cells from single-cell RNA-seq data derived from 33 CRC tumor samples were analyzed by nonnegative matrix factorization (NMF) for 23 m6A RNA methylation regulators. CRC and Immunotherapy cohorts from public repository were used to determine the prognosis and immune response of TME clusters. Results The fibroblasts, macrophages, T and B cells were respectively grouped into 4 to 5 subclusters and then classified according to various biological processes and different marker genes. Furthermore, it revealed that the m6A RNA methylation regulators might be significantly related to the clinical and biological features of CRC, as well as the pseudotime trajectories of main TME cell types. Bulk-seq analysis suggested that these m6A-mediated TME cell subclusters had significant prognostic value for CRC patients and distinguished immune response for patients who underwent ICB therapy, especially for the CAFs and macrophages. Notably, CellChat analysis revealed that RNA m6A methylation-associated cell subtypes of TME cells manifested diverse and extensive interaction with tumor epithelial cells. Further analysis showed that ligand-receptor pairs, including MIF − (CD74 + CXCR4), MIF − (CD74 + CD44), MDK–NCL and LGALS9 − CD45, etc. mediated the communication between m6A associated subtypes of TME cells and tumor epithelial cells. Conclusions Taken together, our study firstly revealed the m6A methylation mediated intercellular communication of the tumor microenvironment in the regulation of tumor growth and antitumor immunomodulatory processes.

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“…To verify the predictive ability of the MHC-II signature on the efficacy of immunotherapy, we collected the transcription and survival data of two additional cohorts treated with immunotherapy from the GEO. These cohorts contained the following: GSE19423, patients with bladder cancer (n = 48) treated with BCG immunotherapy (Kim et al, 2010); GSE176307, patients with bladder cancer (n = 87) treated with anti-PD-L1 drugs (Rose et al, 2021). RNA-seq count data were converted into Transcripts Per Million (TPM) (Wagner et al, 2012) in order to calculate gene signature scores.…”

Section: Data Collection and Preprocessingmentioning

confidence: 99%

MHC-II Signature Correlates With Anti-Tumor Immunity and Predicts anti-PD-L1 Response of Bladder Cancer

Hong

Zhang

et al. 2022

Front. Cell Dev. Biol.

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A large proportion of anti-tumor immunity research is focused on major histocompatibility complex class I (MHC-I) molecules and CD8+ T cells. Despite mounting evidence has shown that CD4+ T cells play a major role in anti-tumor immunity, the role of the MHC-II molecules in tumor immunotherapy has not been thoroughly researched and reported. In this study, we defined a MHC-II signature for the first time by calculating the enrichment score of MHC-II protein binding pathway with a single sample gene set enrichment analysis (ssGSEA) algorithm. To evaluate and validate the predictive value of the MHC class II (MHC-II) signature, we collected the transcriptome, mutation data and matched clinical data of bladder cancer patients from IMvigor210, The Cancer Genome Atlas (TCGA) databases and Gene Expression Omnibus (GEO) databases. Comprehensive analyses of immunome, transcriptome, metabolome, genome and drugome were performed in order to determine the association of MHC-II signature and tumor immunotherapy. We identified that MHC-II signature is an independent and favorable predictor of immune response and the prognosis of bladder cancer treated with immune checkpoint inhibitors (ICIs), one that may be superior to tumor mutation burden. MHC-II signature was significantly associated with increased immune cell infiltration and levels of immune-related gene expression signatures. Additionally, transcriptomic analysis showed immune activation in the high-MHC-II signature subgroup, whereas it showed fatty acid metabolism and glucuronidation in the low-MHC-II signature subgroup. Moreover, exploration of corresponding genomic profiles highlighted the significance of tumor protein p53 (TP53) and fibroblast growth factor receptor 3 (FGFR3) alterations. Our results also allowed for the identification of candidate compounds for combined immunotherapy treatment that may be beneficial for patients with bladder cancer and a high MHC-II signature. In conclusion, this study provides a new perspective on MHC-II signature, as an independent and favorable predictor of immune response and prognosis of bladder cancer treated with ICIs.

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Fibroblast growth factor receptor 3 alterations and response to immune checkpoint inhibition in metastatic urothelial cancer: a real world experience

Cited by 95 publications

References 41 publications

Pyroptosis-Related Signature Predicts Prognosis and Immunotherapy Efficacy in Muscle-Invasive Bladder Cancer

Pyroptosis-Related Signature Predicts Prognosis and Immunotherapy Efficacy in Muscle-Invasive Bladder Cancer

Single-cell N6-methyladenosine regulator patterns guide intercellular communication of tumor microenvironment that contribute to colorectal cancer progression and immunotherapy

MHC-II Signature Correlates With Anti-Tumor Immunity and Predicts anti-PD-L1 Response of Bladder Cancer

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