Identification and validation of an immunotherapeutic signature for colon cancer based on the regulatory patterns of ferroptosis and their association with the tumor microenvironment

Yong Liu ¹, Junzhang Zhao ², Baoxiang Huang ¹

¹Key Laboratory of Computer-Aided Drug Design of Dongguan City, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523710, Guangdong, PR China; Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Guangdong Medical University, Dongguan 523808, Guangdong, PR China.
²Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, Guangdong, PR China.
³Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong, PR China.
⁴Dongguan Institute of Clinical Oncology Research in Dongguan People's Hospital, Dongguan 523018, Guangdong, PR China.
⁵School of Basic Medicine, Guangdong Medical University, Dongguan 523018, Guangdong, PR China.
⁶Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Guangdong Medical University, Dongguan 523808, Guangdong, PR China; National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, The Second Affiliated Hospital, Southern University of Science and Technology, Shenzhen 518112, Guangdong, PR China.

⁰Key Laboratory of Computer-Aided Drug Design of Dongguan City, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523710, Guangdong, PR China; Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Guangdong Medical University, Dongguan 523808, Guangdong, PR China.

Biochimica Et Biophysica Acta. Molecular Cell Research +

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February 22, 2024

View abstract on PubMed

Summary

This study reveals distinct ferroptosis patterns in colon cancer, linking them to the tumor microenvironment and immune phenotypes. A novel ferroptosis-regulated gene score (FRG-score) predicts patient outcomes and immunotherapy response.

Area Of Science

Oncology
Cancer Research
Immunology

Background

Ferroptosis, a regulated form of cell death, plays a role in cancer, but its specific regulatory patterns and impact on the colon cancer microenvironment remain underexplored.
Understanding the ferroptosis landscape is crucial for developing effective immunotherapeutic strategies for colon cancer (CC).

Purpose Of The Study

To identify and characterize ferroptosis regulatory patterns in colon cancer.
To correlate these patterns with tumor microenvironment (TME) cell infiltration and immune phenotypes.
To develop a ferroptosis-regulated gene score (FRG-score) for predicting clinical outcomes and immunotherapy response in CC.

Main Methods

Analysis of 1623 colon cancer samples to identify ferroptosis modification patterns based on ferroptosis-associated genes.
Systematic correlation of identified patterns with TME cell infiltration characteristics and tumor immune phenotypes.
Construction of a ferroptosis-regulated gene score (FRG-score) and validation in immunotherapy cohorts; identification and validation of a hub gene (APOL6).

Main Results

Three distinct ferroptosis patterns were identified: antioxidant defense, iron toxicity, and lipid peroxidation, which strongly correlated with immune-inflamed, immune-excluded, and immune-desert phenotypes.
The FRG-score effectively predicted tumor inflammatory status, subtype, stromal activity, genetic variation, and clinical outcomes.
Patients with low FRG-scores demonstrated significant therapeutic and clinical benefits from immunotherapy. Apolipoprotein L6 (APOL6) was identified as a key drug-sensitive target.

Conclusions

Ferroptosis regulatory patterns are integral to the colon cancer microenvironment and immune landscape.
The FRG-score serves as a valuable tool for predicting patient prognosis and response to immunotherapy in colon cancer.
Targeting key ferroptosis-associated genes like APOL6 presents a potential therapeutic avenue for colon cancer treatment.

Keywords:

APOL6 Colon cancer Drug target Ferroptosis regulation genes Immunotherapy Tumor microenvironment