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Updated: May 5, 2026
Detection of a Circulating MicroRNA Custom Panel in Patients with Metastatic Colorectal Cancer
Published on: March 14, 2019
A multi-dimensional omics framework identifies GPR35 as a driver of M2 macrophage activation and poor prognosis in
Shen Guan1, Liangchen Zhu2, Yue Tian3
1Department of Colorectal Surgery, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China.
Introduction:
Colorectal cancer (CRC) remains a leading cause of global cancer mortality, with therapeutic outcomes heavily reliant on the tumor microenvironment (TME). While immunotherapy has revolutionized treatment for distinct subsets, the mechanisms driving immune evasion in the majority of patients remain elusive.
Methods:
In this study, we constructed a comprehensive single-cell atlas of the CRC TME by integrating multi-cohort scRNA-seq data.
Results:
Through non-negative matrix factorization (NMF), we identified nine intratumoral heterogeneity meta-programs (MPs), among which MP8 was robustly linked to M2 macrophage activation. High-dimensional WGCNA further pinpointed GPR35 as a master regulator within the MP8-associated gene network. Clinical analysis across four independent cohorts validated GPR35 as a significant predictor of poor prognosis. Functionally, GPR35 knockdown in vitro markedly impaired CRC cell proliferation, migration, and invasion. Mechanistically, high GPR35 expression orchestrated an immune-excluded microenvironment characterized by diminished cytotoxic T cell and NK cell recruitment, yet paradoxically elevated immune checkpoint expression. Furthermore, GPR35 expression was negatively correlated with eight established immunotherapy response signatures and associated with aggressive mutational landscapes.
Discussion:
Collectively, our findings identify GPR35 as a novel cancer cell-intrinsic driver of immune evasion and immunotherapy resistance, positioning it as a promising therapeutic target to sensitize "cold" CRC tumors to immune checkpoint blockade.
Insights
This study reveals GPR35 drives immune evasion in colorectal cancer (CRC), hindering immunotherapy. Targeting GPR35 may sensitize cold tumors to treatment, improving outcomes for many CRC patients.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Colorectal cancer (CRC) poses a significant global health challenge, with treatment success often dictated by the tumor microenvironment (TME).
- Current immunotherapies are effective for only a subset of patients, necessitating research into mechanisms of immune evasion.
Purpose of the Study:
- To construct a comprehensive single-cell atlas of the CRC TME.
- To identify key regulators of immune evasion and immunotherapy resistance in CRC.
Main Methods:
- Integration of multi-cohort single-cell RNA sequencing (scRNA-seq) data.
- Application of non-negative matrix factorization (NMF) and weighted gene co-expression network analysis (WGCNA).
- Validation of findings across four independent clinical cohorts.
Main Results:
- Identification of nine intratumoral heterogeneity meta-programs (MPs), with MP8 linked to M2 macrophage activation.
- GPR35 identified as a master regulator of MP8, predicting poor prognosis in CRC patients.
- High GPR35 expression correlated with an immune-excluded TME, reduced cytotoxic T cell infiltration, and resistance to immunotherapy.
Conclusions:
- GPR35 is a novel, cancer cell-intrinsic driver of immune evasion and immunotherapy resistance in CRC.
- GPR35 represents a potential therapeutic target to enhance immunotherapy efficacy in "cold" CRC tumors.
