Abstract
The driver genes regulating T-cell infiltration are important for understanding immune-escape mechanisms and developing more effective immunotherapy. However, researches in this field have rarely been reported in hepatocellular carcinoma (HCC). In the present study, we identified cancer driver genes triggered by copy number alterations such as CDKN2B, MYC, TSC1, TP53, and GSK3B. The T-cell infiltration levels were significantly decreased in both HCC and recurrent HCC tissues compared with the adjacent normal liver tissues. Remarkably, we identified that copy number losses of MAX and TP53 were candidate driver genes that significantly suppress T-cell infiltration in HCC. Accordingly, their downstream oncogenic pathway, cell cycle, was significantly activated in the low T-cell infiltration HCC. Moreover, the chemokine-related target genes by TP53, which played key roles in T-cell recruitment, were also downregulated in HCC with TP53/MAX deletions, suggesting that copy number losses in MAX and TP53 might result in T-cell depletion in HCC via downregulating chemokines. Clinically, the T-cell infiltration levels and chemokines activity could accurately predict the response of sorafenib, and the prognostic outcomes in HCC. In conclusion, the systematic analysis not only facilitates identification of driver genes and signaling pathways involved in T-cell infiltration and immune escape, but also gains more insights into the functional roles of T cells in HCC.
Highlights
Hepatocellular carcinoma (HCC) is a highly aggressive cancer with an increasing incidence, accounting for the majority of all primary liver cancer cases (Kung-Chun Chiu et al, 2020)
We identified a series of cancer driver genes triggered by CNAs such as CDKN2B, MYC, TSC1, TP53, and GSK3B, which were enriched in the frequently amplified and deleted regions, respectively, and well-characterized in several cancers (Zack et al, 2013; Tokheim et al, 2016; Bailey et al, 2018)
With the T-cell infiltration levels in liver normal tissues, hepatocellular carcinoma (HCC), and recurrent HCC tissues, we found T-cell infiltration levels were decreased progressively, showing consistency with previous studies that reduced T-cell infiltration might be associated with poor prognosis (Ye et al, 2019; Pinato et al, 2020)
Summary
Hepatocellular carcinoma (HCC) is a highly aggressive cancer with an increasing incidence, accounting for the majority of all primary liver cancer cases (Kung-Chun Chiu et al, 2020). Prior hepatitis B and/or hepatitis C infection is often considered a major risk factor of HCC, along with alcohol consumption, tobacco use, and obesity (Grandhi et al, 2016). The association between a dysregulated immune system and the development of HCC has been demonstrated in many studies, and changes in the abundance or function of tumor-related immune. It has been reported that cytotoxic T lymphocytes and CD4+ T cells could affect antigen recognition and DNA-based immunization (Grimm et al, 2000). To our knowledge, tumorinfiltrating lymphocytes are an essential component of tumor microenvironment (TME), and a previous study has assessed the clinical significance of tumor-infiltrating NK cells in HCC, successfully relating NK cell abundances to several immune checkpoint proteins (Wu et al, 2020)
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