Integrative molecular characterisation of gallbladder cancer reveals micro-environment-associated subtypes

Integrative genomics highlights opportunities for innovative therapies targeting the tumor microenvironment in gallbladder cancer

“…In contrast, poor prognosis GBC were associated with dysregulation of immune-related pathways, including dysfunctional T cells and T cell exclusion. 5 In agreement with the presence of an immunosuppressive microenvironment, poor prognosis GBC also exhibited expression of markers linked to the activation of transforming growth factor beta (TGFb), a potent immunosuppressive cytokine (Fig. 1).…”

“…The work of Nepal and colleagues, aiming at deciphering the different TIME present in GBC, could thus represent a major step forward for future clinical trial development. 5 Similar analyses were previously done in CCA, highlighting clinically relevant subgroups of patients who may benefit from immunotherapies based on specific TIME. 17 The subgroup of GBC with a better prognosis identified by Nepal and colleagues would, at first glance, appear to be a good target for evaluating ICIs.…”

“…Histomorphological analysis by Nepal and colleagues showed an enrichment of biliary, gastric foveolar and intestinal growth patterns in subtype 1, subtype 2 and subtype 3, respectively. 5 Interestingly, this morpho-molecular subtyping resembles the pattern of intracholecystic papillary neoplasm, the known premalignant lesion of the gallbladder, raising interesting questions regarding the processes of tumor differentiation and malignant transformation. However, independent validation of this finding and identification of tissue biomarkers associated with these histological subtypes would provide additional support for an association of gastric foveolar GBC with good prognosis.…”

“…4 In this issue of Journal of Hepatology, Nepal and colleagues address this issue by establishing a comprehensive landscape of genetic, epigenetic and transcriptomic alterations in a large cohort of patients with GBC. 5 Importantly, by integrating various data from DNA methylation changes, copy number analysis, RNA sequencing and whole exome sequencing, they highlight clinically relevant tumor subgroups associated with prognosis (Fig. 1).…”

“…1). 5 MDSCs have been shown to exhibit strong immunosuppressive effects by upregulating regulatory T cells and immune suppressive cytokines, as well as supporting the conversion of fibroblasts to CAFs. 14 Therefore, the study by Nepal and colleagues sheds new light on the tumor microenvironment of GBC in poor and good outcome subgroups, supporting the hypothesis that immunosuppression and microenvironment remodeling may account for poor patient survival and possibly poor response to immune checkpoint inhibitors (ICIs) (Fig.…”