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T-cell abundance measured by immunoSEQ predicts overall survival in colorectal cancer
Background
Tumor infiltrating lymphocytes measured by expert pathologists are an independent prognostic factor for colorectal cancer. Newer PCR-based techniques to quantify T-cells within macrodissected tumors measure T-cell receptor (TCR) abundance and may have the potential to supplant or augment histopathologic evaluation as a prognostic factor for overall survival.
Methods
Population-based, incident cases of pathologically confirmed adenocarcinoma of the colon or rectum diagnosed between between March 31, 1998 and July 1, 2017 were recruited to the Molecular Epidemiology of Colorectal Cancer study in a geographically defined region of northern Israel, signed written informed consent, completed a validated clinical and epidemiologic survey instrument, and were followed longitudinally. Archived paraffin blocks were retrieved, and recut slides were reviewed by a single pathologist to circle areas of adequate tumor cellularity. DNA was extracted from macrodissected recut slides, and immunoSEQ™ (Adaptive Biotechnologies, Seattle, WA) was performed to sequence the hypervariable CDR3β region of the T-cell receptor. TCR abundance was quantified as the proportion of cells from the sample that express productive surface CDR3β amino acid sequences. Cox-proportional hazards models were used to estimate hazard ratios after appropriate transformation of the raw data.
Results
6,006 cases were recruited, and 2,750 cases had sufficient tissue and adequate DNA extracted from formalin-fixed, paraffin-embedded tumor blocks to perform immunoSeq assays. Median follow-up time was 7.25 years. TCR abundance was statistically significantly associated with colorectal cancer overall survival. TCR abundance (as a continuous variable) yielded an unadjusted hazard ratio (HR) for overall survival of 0.914 (95% confidence interval: 0.877-0.954; p-value=0.00003). After adjustment for age, sex, stage, and microsatellite instability, TCR abundance remained an independent, statistically significant predictor of overall survival (HR = 0.936, 95% confidence interval: 0.897-0.977, p=0.0002). The highest quartile of TCR abundance (contrasted with lowest quartile) was strongly and significantly associated with favorable overall survival with a HR of 0.782 (95% confidence interval: 0.683-0.895, p=0.00004).
Conclusions
TCR abundance as measured by Adaptive immunoSEQ™ is a statistically significant, independent prognostic factor for overall survival of colorectal cancer.
Legal entity responsible for the study
The authors.
Funding
The Molecular Epidemiology of Colorectal Cancer Study (MECC) was supported by the National Cancer Institute of the National Institutes of Health through grants: R01CA197350, R01CA81488, P30CA014089, U19CA148107, P01CA196569 and a generous gift from Daniel and Maryann Fong. Research reported here is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Disclosures
All authors have declared no conflicts of interest.
