Abstract
Colorectal cancer (CRC) is a major cause of cancer mortality and morbidity. Despite advances in chemotherapy and targeted therapy, unsustainable clinical benefit was noted due to recurrence and therapy resistance. The immune status of the cancer patient may affect the effectiveness of disease treatments. The dynamic change in the T-cell receptor (TCR) repertoire might be a clinical parameter for monitoring treatment responses. In this study, we aimed to determine the characteristics and clinical significance of the TCR repertoire in patients with unresectable metastatic colorectal cancer (mCRC). Herein, we comprehensively profile 103 peripheral blood samples from 20 healthy controls and 16 CRC patients with a follow-up of 98 to 452 days to identify hypervariable rearrangements of the TCRα and TCRβ repertoires using high-throughput sequencing. We found that TCRα repertoires, TCRβ repertoires, and CDR3 clonotypes were altered in mCRC patients compared with healthy controls. The diversity of TCR repertoires and CDR3 clonotypes decreased in most mCRC patients after therapy. Furthermore, compared with baseline TCR diversity, patients whose TCR diversity dropped considerably during therapy had better treatment responses, including lower CEA and CA19-9 levels and smaller tumor sizes. TCR baseline diversity was also significantly associated with partial response (PR) status (odds ratio: 5.29, p = 0.04). In conclusion, the present study demonstrated the association between dynamic changes in TCR diversity during chemotherapy and clinical outcomes as well as the potential utility of the TCR repertoire in predicting the prognosis of cancer treatment.
Highlights
Colorectal cancer (CRC) is one of the most common cancers worldwide
Our study demonstrated that the dynamic change in TCRa and TCRb diversity was correlated with the levels of tumor markers (CEA and cell surface antigen 19-9 (CA19-9)) and tumor size after medical treatment, which demonstrated the prognostic potential of the T-cell receptor (TCR) repertoire for monitoring treatment responses in CRC
TCRa dynamics analysis showed a more effective approach for distinguishing patient treatment response than TCRb variation in our cohort. These findings provide solid methodology and observations of decreased TCR diversity correlating with response to chemotherapy in mCRC and an indication of correlation with response to therapy, and the noninvasive repertoire profiling using peripheral blood provides useful clinical information and expands the understanding of oncoimmunology
Summary
Colorectal cancer (CRC) is one of the most common cancers worldwide. It remains a major cause of cancer mortality and morbidity among men and women globally [1, 2]. Imaging technology, including computed tomography (CT) or magnetic resonance imaging (MRI), can be used to measure the tumor size in follow-up patients. These examinations cannot be performed frequently due to radiation side effects [3]. Serum carcinoembryonic antigen (CEA) and carbohydrate cell surface antigen 19-9 (CA19-9) are recommended as tumor markers in CRC for tumor detection and monitoring of treatment responses. Their sensitivity and specificity issues limit their clinical usefulness [4,5,6]. Biomarker studies include early detection of therapy resistance, and ensuring that patients are exposed to as many active therapies as possible is necessary
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