Pan-cancer analyses and molecular subtypes based on the cancer-associated fibroblast landscape and tumor microenvironment infiltration characterization reveal clinical outcome and immunotherapy response in epithelial ovarian cancer

Abstract

BackgroundCancer-associated fibroblasts (CAFs) are essential components of the tumor microenvironment (TME). These cells play a supportive role throughout cancer progression. Their ability to modulate the immune system has also been noted. However, there has been limited investigation of CAFs in the TME of epithelial ovarian cancer (EOC).MethodsWe comprehensively evaluated the CAF landscape and its association with gene alterations, clinical features, prognostic value, and immune cell infiltration at the pan-cancer level using multi-omic data from The Cancer Genome Atlas (TCGA). The CAF contents were characterized by CAF scores based on the expression levels of seven CAF markers using the R package “GSVA.” Next, we identified the molecular subtypes defined by CAF markers and constructed a CAF riskscore system using principal component analysis in the EOC cohort. The correlation between CAF riskscore and TME cell infiltration was investigated. The ability of the CAF riskscore to predict prognosis and immunotherapy response was also examined.ResultsCAF components were involved in multiple immune-related processes, including transforming growth factor (TGF)-β signaling, IL2-STAT signaling, inflammatory responses, and Interleukin (IL) 2-signal transducer and activator of transcription (STAT) signaling. Considering the positive correlation between CAF scores and macrophages, neutrophils, and mast cells, CAFs may exert immunosuppressive effects in both pan-cancer and ovarian cancer cohorts, which may explain accelerated tumor progression and poor outcomes. Notably, two distinct CAF molecular subtypes were defined in the EOC cohort. Low CAF riskscores were characterized by favorable overall survival (OS) and higher efficacy of immunotherapy. Furthermore, 24 key genes were identified in CAF subtypes. These genes were significantly upregulated in EOC and showed a strong correlation with CAF markers.ConclusionsIdentifying CAF subtypes provides insights into EOC heterogeneity. The CAF riskscore system can predict prognosis and select patients who may benefit from immunotherapy. The mechanism of interactions between key genes, CAF markers, and associated cancer-promoting effects needs to be further elucidated.

Normal Uterine Fibroblast Are Reprogramed into Ovarian Cancer-Associated Fibroblasts by Ovarian Tumor-derived Conditioned Media

“…Moreover, the stromal cells were ranked according to three distinct CAF scores 36–38 and robustly showed that both CM-CAFs and OC-CAFs significantly ranked higher for CAF scores than HUFs (Figure 4D). Similarly, considering the clear implication of CAFs in ECM remodeling, three ECM scores were produced 39,40 , and again both CM-CAFs and OC-CAFs significantly ranked higher for ECM scores than HUFs (Figure 4E).…”

“…All volcano plots were built using the EnhancedVolcano R package and all heatmaps were built using the ComplexHeatmap R package. Using the RNA-sequencing results for HUFs, CM-CAFs, and OC-CAFs with the GSVA R package, an ECM score was produced using three gene sets from the GSEA website for the core, associated, and complete Naba matrisome and a CAF score was produced from gene sets used in previous studies: 24 carcinoma-associated fibroblast genes upregulated by MSCs grown in tumor conditioned media 37 ; 7 CAF markers used to identify two CAF subtypes 36 ; and 5 CAF markers used to identify four CAF subtypes 38 . A dataset of OC patients from Tothill et al 35 was obtained through accession GSE9899.…”

Stromal depletion by TALEN-edited universal hypoimmunogenic FAP-CAR T cells enables infiltration and anti-tumor cytotoxicity of tumor antigen-targeted CAR-T immunotherapy

“…The copyright holder for this preprint this version posted February 27, 2023. ; https://doi.org/10.1101/2023.02. 27.529938 doi: bioRxiv preprint α (FAP) 18 , that correlates with both poor prognosis and response to immunotherapies 19,20 .…”

“…Together, these physical and chemical barriers foster T-cell exclusion and exhaustion 14, 15 . CAF-rich tumors are thus often ‘cold’ nonimmunogenic tumors with a T-cell deficient immune desert signature landscape 16, 17 Corroboratively, over 90% of epithelial cancers including breast, colorectal, pancreatic and lung adenocarcinomas express the CAF-specific surface marker, fibroblast activation protein-α (FAP) 18 , that correlates with both poor prognosis and response to immunotherapies 19, 20 . Fortunately, other than a small fraction of cells in the proliferative stage of placenta and uterine stroma, embryonic tissue and multipotent bone marrow stromal cells, FAP is not expressed in healthy adult tissues 21 .…”

“…Corroboratively, over 90% of epithelial cancers including breast, colorectal, pancreatic and lung adenocarcinomas express the CAF-specific surface marker, fibroblast activation protein-α (FAP) 18 , that correlates with both poor prognosis and response to immunotherapies 19,20 .…”