Premium
HBV‐specific CD4+ cytotoxic T cells in hepatocellular carcinoma are less cytolytic toward tumor cells and suppress CD8+ T cell‐mediated antitumor immunity
Author(s) -
Meng Fanzhi,
Zhen Shoumei,
Song Bin
Publication year - 2017
Publication title -
apmis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.909
H-Index - 88
eISSN - 1600-0463
pISSN - 0903-4641
DOI - 10.1111/apm.12704
Subject(s) - cytotoxic t cell , granzyme b , il 2 receptor , interleukin 21 , granzyme , cd8 , biology , cancer research , immunology , immunotherapy , t cell , immune system , perforin , in vitro , biochemistry
In East Asia and sub‐Saharan Africa, chronic infection is the main cause of the development of hepatocellular carcinoma, an aggressive cancer with low survival rate. Cytotoxic T cell‐based immunotherapy is a promising treatment strategy. Here, we investigated the possibility of using HBV ‐specific CD 4 + cytotoxic T cells to eliminate tumor cells. The naturally occurring HBV ‐specific cytotoxic CD 4 + and CD 8 + T cells were identified by HBV peptide pool stimulation. We found that in HBV ‐induced hepatocellular carcinoma patients, the HBV ‐specific cytotoxic CD 4 + T cells and cytotoxic CD 8 + T cells were present at similar numbers. But compared to the CD 8 + cytotoxic T cells, the CD 4 + cytotoxic T cells secreted less cytolytic factors granzyme A (GzmA) and granzyme B (GzmB), and were less effective at eliminating tumor cells. In addition, despite being able to secrete cytolytic factors, CD 4 + T cells suppressed the cytotoxicity mediated by CD 8 + T cells, even when CD 4 + CD 25 + regulator T cells were absent. Interestingly, we found that interleukin 10 ( IL ‐10)‐secreting Tr1 cells were enriched in the cytotoxic CD 4 + T cells. Neutralization of IL ‐10 abrogated the suppression of CD 8 + T cells by CD4 + CD25 − T cells. Neither the frequency nor the absolute number of HBV ‐specific CD 4 + cytotoxic T cells were correlated with the clinical outcome of advanced stage hepatocellular carcinoma patients. Together, this study demonstrated that in HBV ‐related hepatocellular carcinoma, CD 4 + T cell‐mediated cytotoxicity was present naturally in the host and had the potential to exert antitumor immunity, but its capacity was limited and was associated with immunoregulatory properties.