Immune profiling of the macroenvironment in colorectal cancer unveils systemic dysfunction and plasticity of immune cells

IF 7.9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine Pub Date : 2025-02-11 DOI:10.1002/ctm2.70175

Haoxian Ke, Peisi Li, Zhihao Li, Xian Zeng, Chi Zhang, Shuzhen Luo, Xiaofang Chen, Xinlan Zhou, Shichen Dong, Shaopeng Chen, Junfeng Huang, Ming Yuan, Runfeng Yu, Shubiao Ye, Tuo Hu, Zhonghui Tang, Dongbin Liu, Kui Wu, Xianrui Wu, Ping Lan

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Abstract

Background

Tumour immune macroenvironment is comprised of tumour and surrounding organs responding to tumourigenesis and immunotherapy. The lack of comprehensive analytical methods hinders its application for prediction of survival and treatment response in colorectal cancer (CRC) patients.

Methods

Cytometry by time-of-flight (CyTOF) and RNA-seq was applied to characterise immune cell heterogeneity in a discovery cohort including tumour, blood and intestinal architecture comprising epithelium, lamina propria, submucosa, muscularis propria of normal bowel and tumour–adjacent bowel tissues. Immunoprofiling was also validated by a validation cohort using single-cell RNA sequencing, spatial transcription, CyTOF and multiplex immunofluorescent staining.

Results

Based on cell phenotype and transcription, we identify distinct immunotypes in the CRC macroenvironment including blood, tumour and different intestinal architecture, showing disturbed immune cell compositions, increasing expression of immunosuppressive markers and cell–cell interactions contributing to immunosuppressive regulation. Furthermore, we evaluate immune macroenvironment influencing factors including tertiary lymphoid structures (TLSs), consensus molecular subtypes (CMSs) and immune checkpoint inhibitors (ICIs). TLS presence fuels anti-tumour immunity by promoting CD8⁺ T cell infiltration and altering activation or suppression of T cell systematically. TLS presence correlates with patient survival, intrinsic CMS and therapeutic efficacy of ICI. PD-1 and CD69 expressed in effector memory CD8⁺ T cells from blood can predict TLS presence in the CRC macroenvironment, serving as potential biomarkers for stratifying CRC patients into immunotherapy.

Conclusions

Our findings provide insights into the CRC immune macroenvironment, highlighting immune cell suppression and activation in tumourigenesis. Our study illustrates the potential utility of blood for predicting immunotherapy response.

Key points

Distinct immunotypes are identified in the CRC macroenvironment.
TLS and immunotherapy exert influence on the immune macroenvironment.
TLS presence correlates with patient survival, CMS and therapeutic efficacy of ICI.
PD-1 and CD69 expressed in CD8+ Tem from blood can predict TLS presence in the CRC macroenvironment.

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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.