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Dysregulation of the Hippo Pathway in Cancer Associated Fibroblasts is Associated with anti-PD-L1 atezolizumab Resistance

ABSTRACT: The use of immunotherapy in solid tumors has significantly improved the outcomes and quality of life for cancer patients. However, a substantial fraction of patients remain unresponsive, highlighting the urgent need to identify novel mechanisms of resistance to enhance immune-centric, chemo-free treatment regimens. In this study, we investigate associations with immunotherapy resistance by integrating RNAseq data from 2800 bladder cancer patients enrolled in the IMvigor trials, focusing on resistance to the anti-PD-L1 therapy atezolizumab, along with single-cell data from 200 patient samples and healthy donors. To expand the analysis to a massive collection of over 100M cells from hundreds of diverse single cell studies, we present Firmament, a newly developed method to efficiently identify cell populations that show enrichment for expression of gene signatures. Through these analyses, we identify the Hippo pathway as critically associated with immunotherapy resistance in bladder cancer and other solid tumors. Our findings indicate that Hippo dysregulation in stromal cells, rather than cancer cells, drives the high YAP/TAZ signal in these tumors. We specifically identify dysregulated Hippo signaling in cancer-associated fibroblasts compared to healthy donor fibroblasts. These insights will be important for developing novel therapeutic combinations to improve outcomes for patients with solid tumors treated with immune checkpoint inhibitors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE313827 | GEO | 2026/02/20

REPOSITORIES: GEO

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Project description:Full title: Predictive Gene Signatures as Strong Prognostic Indicators of the Effectiveness of Bacillus Calmetteâ??GuÃ©rin (BCG) Immunotherapy in Primary pT1 Bladder Cancers Intravesical BCG immunotherapy is effective in prevention of recurrence and progression in many cases of non-muscle invasive bladder cancer, but many patients fail to respond. This study identified predictive gene signatures in primary pT1 bladder cancer with BCG immunotherapy. Fourty-Eight patients with primary pT1 bladder cancer treated with BCG immunotherapy were used. Microarray gene expression analysis of the 48 primary bladder cancers was carried out. Predictive gene signatures were individually selected based on the recurrence and progression status. Among 43,148 unique genes, 424 and 287 candidate predictive genes that could predict recurrence and progression, respectively, were selected. Time to recurrence or progression was shorter for patients with poor-predictive gene signatures than good-predictive gene signatures (log-rank test, p <0.001, respectively). Validation of predictive gene signatures with RT-PCR was nearly identical to those of microarray (log-rank test, p <0.05, respectively). In multivariate regression analysis, predictive gene signatures were the only independent predictors of recurrence (HR 3.38, p = 0.048) or progression (HR 10.49, p = 0.048) in validation cohorts. Predictive gene signatures have strong diagnostic value for determining the response to intravesical BCG immunotherapy in primary pT1 bladder cancer. Keywords: Gene expression, Bladder cancer, BCG Total RNA, extracted from the fresh frozen tissues of 48 pT1 bladder cancers, was isolated by TRIzol reagent (Life Technologies, NY, USA), according to the manufacturer's protocol. The quality and integrity of the RNA were confirmed by agarose gel electrophoresis and ethidium bromide staining, followed by visual examination under ultraviolet light. Five-hundred nanograms of total RNA were used for labeling hybridization according to the manufacturerâ??s protocol (Illumina HumanWG-6 BeadChip, version 2, Illumina, Inc., San Diego, CA, USA). Arrays were scanned with an Illumina Bead Array Reader confocal scanner (BeadStation 500GXDW; Illumina, Inc.) according to the manufacturer's instructions. Initial microarray gene expression data were obtained using Bead Studio software with gene expression analysis module (version 3.1.3, Illumina, Inc.).

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Dysregulation of the Hippo Pathway in Cancer Associated Fibroblasts is Associated with anti-PD-L1 atezolizumab Resistance

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