Integrated Multi-Omics Profiling Identifies an Immunotherapy Vulnerable and Prognostic Associated Subtype in...

Area of Science:

• Oncology
• Genomics
• Immunology

Background:

• Cholangiocarcinoma (CCA) is an aggressive cancer with limited treatment options.
• Molecular heterogeneity and the tumor immune microenvironment significantly impact CCA progression and treatment response.
• Current stratification methods are insufficient for guiding personalized treatment decisions in CCA.

Purpose of the Study:

• To perform integrated multi-omics profiling and immunohistochemical validation in a large cohort of CCA patients.
• To identify clinically relevant molecular subtypes of CCA based on multidimensional data.
• To explore the potential of these subtypes in guiding precision immunotherapy.

Main Methods:

• Integrated multi-omics profiling (genomic, epigenomic, transcriptomic, immune) on 424 CCA patients.
• Immunohistochemical validation of identified molecular features.
• Analysis of clinical and immunological characteristics for each subtype.

Main Results:

• Four distinct molecular subtypes of CCA were identified: C1 (proliferation), C2 (immune-suppressed), C3 (immune-activated), and C4 (immune-excluded).
• The C3 subtype demonstrated high responsiveness to immune checkpoint blockade (ICB) with a 75% overall response rate.
• ATP2B1 was validated as a novel prognostic biomarker, and a 160-gene classifier was developed for subtype prediction.

Conclusions:

• The identified molecular subtypes offer a novel framework for understanding CCA heterogeneity.
• The C3 subtype's exceptional ICB response, independent of conventional biomarkers, highlights the potential for precision immunotherapy in CCA.
• This classification system can guide treatment decisions, particularly for immunotherapy selection in CCA patients.