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DeCAF redefines fibroblast states uncovering multidimensional tumor-stroma relationships driving clinical tumor progression and immunotherapy response [RNA-Seq]

ABSTRACT: Cancer-associated fibroblast (CAF) heterogeneity within pancreatic ductal adenocarcinoma (PDAC) has been previously assessed through single-cell RNA sequencing (scRNAseq) to discover distinct CAF populations such as myCAFs and iCAFs. While useful as a biological framework, no studies have conclusively and robustly demonstrated a correlation of CAF subpopulations with clinical prognosis or therapy response. We define restraining (rest) and promoting (pro) CAFs in patient samples that are both prognostic and predictive of therapy response in disparate tumor types. Using a single sample classifier, DeCAF, we uncover distinct clinical and spatial interactions between pro- and restCAF subtypes and basal-like and classical tumor subtypes that support tumor stroma crosstalk where basal-like tumors are enriched in proCAFs and classical tumors are enriched in restCAFs. Finally, we find striking differences in the immune contexture of pro- and restCAF tumors where restCAF dominant tumors are enriched in patients who respond to immune checkpoint inhibition (ICI) in two large clinical trials, and proCAF dominant tumors are enriched in patients who respond to myeloid inhibition. This work is the first to define CAF subtypes that are clinically robust, prognostic, predictive of immunotherapy response, and associate with tumor molecular subtype.

ORGANISM(S): Homo sapiens

PROVIDER: GSE310957 | GEO | 2025/12/18

REPOSITORIES: GEO

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Project description:Novel immunotherapy combination therapies have improved outcomes for patients with hepatocellular carcinoma (HCC), but responses are limited to a subset of patients. Little is known about the inter- and intra-tumor heterogeneity in cellular signaling networks within the HCC tumor microenvironment (TME) that underlie responses to modern systemic therapy. We applied spatial transcriptomics (ST) profiling to characterize the tumor microenvironment in HCC resection specimens from a prospective clinical trial of neoadjuvant cabozantinib, a multi-tyrosine kinase inhibitor that primarily blocks VEGF, and nivolumab, a PD-1 inhibitor in which 5 out of 15 patients were found to have a pathologic response at the time of resection. ST profiling demonstrated that the TME of responding tumors was enriched for immune cells and cancer associated fibroblasts (CAF) with pro-inflammatory signaling relative to the non-responders. The enriched cancer-immune interactions in responding tumors are characterized by activation of the PAX5 module, a known regulator of B cell maturation, which colocalized with spots with increased B cell markers expression suggesting strong activity of these cells. HCC-CAF interactions were also enriched in the responding tumors and were associated with extracellular matrix (ECM) remodeling as there was high activation of FOS and JUN in CAFs adjacent to tumor. The ECM remodeling is consistent with proliferative fibrosis in association with immune-mediated tumor regression. Among the patients with major pathologic response, a single patient experienced early HCC recurrence. ST analysis of this clinical outlier demonstrated marked tumor heterogeneity, with a distinctive immune-poor tumor region that resembles the non-responding TME across patients and was characterized by HCC-CAF interactions and expression of cancer stem cell markers, potentially mediating early tumor immune escape and recurrence in this patient. These data show that responses to modern systemic therapy in HCC are associated with distinctive molecular and cellular landscapes and provide new targets to enhance and prolong responses to systemic therapy in HCC.

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DeCAF redefines fibroblast states uncovering multidimensional tumor-stroma relationships driving clinical tumor progression and immunotherapy response [RNA-Seq]

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