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Inflammatory cancer-associated fibroblasts (iCAFs) are closely related to progression, anticancer therapeutic resistance, and poor prognosis of bladder cancer (BCa). However, the functional role of iCAFs in BCa has been poorly studied. In our study, two BCa scRNA-seq datasets (GSE130001 and GSE146137) were obtained and integrated by the Seurat pipeline. Based on reported markers (COL1A1 and PDGFRA), iCAFs were identified and the related signature of 278 markers was developed. Following unsupervised consensus clustering, two molecular subtypes of TCGA-BLCA were identified and characterized by distinct dysregulated cancer hallmarks, immunological tumor microenvironments, prognoses, responses to chemotherapy/immunotherapy, and stemness. Subsequently, the robustness of the signature-based clustering, in terms of prognosis and therapeutic response prediction, was validated in a GEO-meta cohort with seven independent GEO datasets of 519 BCa patients, and three immune checkpoint inhibitor (ICI)-treated cohorts. Considering the heterogeneity, re-clustering of iCAFs was performed and a subpopulation, named “LOXL2+ iCAFs”, was identified. Co-culture CM derived from LOXL2 overexpression/silencing CAFs with T24 cells revealed that overexpression of LOXL2 in CAFs promoted while silencing LOXL2 inhibited the proliferation, migration, and invasion of T24 cells through IL32. Moreover, the positive correlation between LOXL2 and CD206, an M2 macrophage polarization marker, has been observed and validated. Collectively, integrated single-cell and bulk RNA sequencing analyses revealed an iCAF-related signature that can predict prognosis and response to immunotherapy for BCa. Additionally, the hub gene LOXL2 may serve as a promising target for BCa treatment.

Objective: Considering the striking evidence revealed by immunotherapy in advanced or metastatic bladder cancer, investigators have explored neoadjuvant immunotherapy and chemoimmunotherapy in muscle-invasive bladder cancer (MIBC). Currently, there have been a large number of studies reporting varied efficacy and safety of these approaches. Herein, we pooled the available evidence in terms of oncological outcomes (pathological complete response [pCR] and pathological partial response [pPR]) and safety outcomes (immune-related adverse events [irAEs], treatment-related adverse events [TRAEs]), through a systematic review and meta-analysis. Method: We searched PubMed, Embase, Cochrane Library, and American Society of Clinical Oncology meeting abstracts to identify relevant studies up to June 2022. Studies were included if they evaluated the neoadjuvant immunotherapy or chemoimmunotherapy in MIBC and reported at least the pCR. Results: A total of 22 records involving 843 patients were included. For pCR of immunotherapy, the pooled rate of immune checkpoint inhibitor (ICI) monotherapy and dual-ICIs therapy was 24% (95% confidence interval [CI]: 15.3% - 32.8%) and 32.1% (95%CI: 20.6% - 43.7%), respectively. For pCR of chemoimmunotherapy, the overall pooled rate was 42.6% (95% CI: 34.9% - 50.2%). Subgroup of gemcitabine/cisplatin (GC) plus ICI had a pCR rate of 41.7% (95%CI: 35.8% - 47.5%). In terms of safety, the pooled rate of Grade=3 irAEs was 11.7% (95% CI: 6.5%-16.9%). In subgroup analysis, the Grade=3 irAEs rate of ICI monotherapy, dual-ICIs therapy, and GC plus ICI therapy was 7.4% (95% CI: 4.3%-10.5%), 30.3% (95% CI: 15.3%-45.3%), and 14.5% (95% CI: 3.5% - 25.4%), respectively. Besides, the pooled Grade=3 TRAEs rate for chemoimmunotherapy was 32.4% (95% CI: 13.1% - 51.6%). Conclusion: Neoadjuvant immunotherapy and chemoimmunotherapy were effective and safe in the treatment of MIBC. Compared to ICI monotherapy, dual-ICIs therapy or chemoimmunotherapy can improve the response rate, while increasing the morbidity of Grade= 3 irAEs or Grade= 3 TRAEs. [ABSTRACT FROM AUTHOR]