Abstract
Different subsets of lymphocytes have the capacity to promote or counteract the progression of solid cancers, including hepatocellular carcinoma (HCC). Therefore, to determine the infiltrative ability and functional status of major immune cell subtypes into tumor may lead to novel insights from the perspective of immunotherapy. After obtaining single cell suspensions from freshly collected specimens of HCC tumor, along with paired peritumor tissues and peripheral blood mononuclear cells (PBMCs) from 14 patients, we flow-cytometrically identified and quantified the relative frequencies of lymphocyte subsets within the tissues of origin. We found that the recruitment in the tumor of cytotoxic cells, namely the terminally differentiated CD4+ and CD8+ T cells (TEFF), is impaired, whereas the effector memory CD4+ T cells (TEM) are more attracted in this site. Concerning the other subsets, the frequency of NK CD56hi and NKT CD56hi cells infiltration in the tumor is increased, whereas that of NKT CD56low is reduced. Although CD4+ and CD8+ T cells settled in the tumor show a higher degree of activation than the circulating counterpart, they occur with a more exhausted phenotype. Overall, these data demonstrate the prevalently immunosuppressive nature of HCC microenvironment, and prompt us to search for strategies to enhance the activity of anti-tumor immune cell subsets.
Highlights
Hepatocellular carcinoma (HCC) ranks as the third leading cause of cancer-related deaths worldwide and one of the most common cancers; it occurs primarily in patients with underlying chronic liver disease and cirrhosis
When we analyzed the infiltration of immune cells (CD45+ ) in the tumor tissue and peritumor, we found that the percentage of CD45+ cells in the peritumor is higher than that in the tumor itself (Figure 1a), showing that the liver is considered as an immunological organ, the infiltration of immune cells to the tumor site is impaired
We found that the proportions of CD4+ TN were slightly increased in the blood of hepatocellular carcinoma (HCC) patients as compared to healthy controls (18.06 ± 5.21 vs. 14.24 ± 5.80), and TCM were decreased (10.24 ± 1.84 vs. 15.36 ± 6.87 in controls) (Table 4 and Figure 3c), whereas the proportions of TEM and effector cells terminally differentiated effectors (TEFF) were similar
Summary
Hepatocellular carcinoma (HCC) ranks as the third leading cause of cancer-related deaths worldwide and one of the most common cancers; it occurs primarily in patients with underlying chronic liver disease and cirrhosis. HCC patients had limited treatment options, including only tumor resection, liver transplantation, thermo-ablation and trans-arterial chemoembolization (TACE), but the five-year survival is poor compared with other malignancies and the rate of tumor recurrence after surgery is very high (70–80% of cases) [1,2]. A multikinase inhibitor, the only multi-targeted pharmaceutical agent, was approved for the treatment of patients with advanced HCC in. 2007 [3], but it increases patient survival by only three months in advanced stage disease [4]. It has various side effects including alopecia, arthralgia, diarrhea, fatigue, headache and hypertension [5,6]; improved therapeutic strategies are urgently needed. The other major problem in the treatment of HCC is the onset of resistance to chemotherapeutic drugs, and even multi-drug resistance [7,8].
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