期刊
JOURNAL FOR IMMUNOTHERAPY OF CANCER
卷 9, 期 9, 页码 -出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/jitc-2021-002671
关键词
biomarkers; tumor; CD8-positive T-lymphocytes; gastrointestinal neoplasms; genetic markers; lymphocytes; tumor-infiltrating
资金
- National Basic Research Program of China (973 Program) [2015CB554001]
- National Natural Science Foundation of China [81972245, 81902877]
- Natural Science Fund for Distinguished Young Scholars of Guangdong Province [2016A030306002]
- Tip-top Scientific and Technical Innovative Youth Talents of Guangdong special support program [2015TQ01R454]
- Sun Yat-Sen University Clinical Research 5010 Program [2018026]
- Natural Science Foundation of Guangdong Province [2018A0303130303, 2021A1515010134]
- 'Five Five' Talent Team Construction Project of the Sixth Affiliated Hospital of Sun Yat-Sen University [P20150227202010244, P20150227202010251]
- Excellent Talent Training Project of the Sixth Affiliated Hospital of Sun Yat-sen University [R2021217202512965]
- Program of Introducing Talents of Discipline to Universities, National Key Clinical Discipline (2012)
- National Cancer Institute
- National Institutes of Health (NIH) [U01 CA167551]
- US National Cancer Institute
This study developed a DNA methylation-based signature for CD8+ TILs in colorectal cancer, which showed a strong association with prognosis and immune markers. The QASM assay developed for CD8+ MeTIL markers provided a quantitative and accurate measurement of CD8+ TILs distribution in tumor tissues, indicating potential as a biomarker for therapeutic approaches, including immunotherapy.
Background Tumor-infiltrating lymphocytes (TILs), especially CD8+ TILs, can be used for predicting immunotherapy responsiveness and survival outcome. However, the evaluation of CD8+ TILs currently relies on histopathological methodology with high variability. We therefore aimed to develop a DNA methylation signature for CD8+ TILs (CD8+ MeTIL) that could evaluate immune response and prognosis in colorectal cancer (CRC). Methods A CD8+ MeTIL signature score was constructed by using CD8+ T cell-specific differentially methylated positions (DMPs) that were identified from Illumina EPIC methylation arrays. Immune cells, colon epithelial cells, and two CRC cohorts (n=282 and 335) were used to develop a PCR-based assay for quantitative analysis of DNA methylation at single-base resolution (QASM) to determine CD8 + MeTIL signature score. Results Three CD8+ T cell-specific DMPs were identified to construct the CD8+ MeTIL signature score, which showed a dramatic discriminability between CD8+ T cells and other cells. The QASM assay we developed for CD8+ MeTIL markers could measure CD8+ TILs distributions in a fully quantitative, accurate, and simple manner. The CD8+ MeTIL score determined by QASM assay showed a strong association with histopathology-based CD8+ TIL counts and a gene expression-based immune marker. Furthermore, the low CD8+ MeTIL score (enriched CD8+ TILs) was associated with MSI-H tumors and predicted better survival in CRC cohorts. Conclusions This study developed a quantitative DNA methylation-based signature that was reliable to evaluate CD8+ TILs and prognosis in CRC. This approach has the potential to be a tool for investigations on CD8+ TILs and a biomarker for therapeutic approaches, including immunotherapy.
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