Abstract
Several studies have demonstrated that the T-cell receptor (TCR) repertoire is associated with prognosis and immune therapy response in several types of cancer. However, the comprehensive features of TCR repertoire in tumor-infiltrating and circulating T cells, as well as its clinical significance of diagnosis in hepatocellular carcinoma (HCC) patients, are still unknown. In this study, we perform paired tumor/peritumoral tissues and peripheral blood samples from 58 patients with HCC and sequenced them with high-throughput TCR to comprehensively analyze the characteristics of TCR and the clinical significance of peripheral TCR sequence. By exploring the abundance and diversity of TCR repertoires, we observe that there was a significantly higher TCR diversity in peripheral blood than in tumoral and peritumoral tissues, while tumoral and peritumoral tissues showed similar TCR diversity. A substantial difference in the usage frequencies of several Vβ, Jβ genes, and TCRβ VJ pairings was found among three types of tissues. Moreover, we reveal that HCC patients have a unique profile of TCR repertoire in peripheral blood in contrast to healthy individuals. We further establish an HCC diagnostic model based on TCRβ VJ pairing usage in peripheral blood, which yields a best-fit area under the curve (AUC) of 0.9746 ± 0.0481 (sensitivity = 0.9675 ± 0.0603, specificity = 0.9998 ± 0.0007, average of 100 repeats) in the test set. Our study describes the characteristics of tissue infiltration and circulating T-cell bank in patients with HCC and shows the potential of using circulating TCR sequence as a biomarker for the non-invasive diagnosis of patients with HCC.
Highlights
We found that the Tcell receptor beta locus (TCRb) complementarity-determining region 3 (CDR3) diversity in peripheral blood was higher than those in the other two tissues
To explore the heterogeneity of T-cell receptor (TCR) features among different tissue types in hepatocellular carcinoma (HCC) patients, we performed TCR sequencing of 40 tumor samples (T), 37 adjacent non-tumor tissue samples (N), and 43 peripheral blood samples (B) collected from 58 patients diagnosed with HCC
As T cells recognize tumor antigens via a diverse range of TCRs, by analyzing features of the TCR repertoire containing TCRb CDR3 and VJ genes, we may deepen our understanding of cancer progression and immune response in the tumor microenvironment
Summary
Liver cancer is the seventh most frequently diagnosed cancer and the third cause of cancer death worldwide, accounting for 905,677 new cases and 830,180 deaths in 2020 [1, 2]. Occupying 75%–90% of cases, hepatocellular carcinoma (HCC) represents the most common type of liver cancer [3, 4]. There are limited therapeutic options for patients with advanced-stage HCC, their general survival time is only 6 months [7]. The high recurrent rate and poor survival are major obstacles to improving the clinical outcome of HCC patients [8–11]. Several molecular markers, such as Glypican-3 (GPC3), Des-g-carboxyprothrombin (DCP), and Osteopontin (OPN), have been reported as potential diagnostic or prognostic markers of HCC, none has translated into routine clinical practice because of their limited accuracy in predicting HCC progression [12]. As for alpha-fetoprotein (AFP), it is the most widely used non-invasive biomarker for HCC diagnosis, and there are still about 30% to 40% of HCC patients who are AFP negative [13, 14]. Identifying more accurate biomarkers to facilitate early diagnosis or monitoring the prognosis of HCC is an urgent need [15]
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