Abstract
CD8+ T cell-mediated immune response plays an important role in inhibiting progression of hepatocellular carcinoma (HCC). For strategic immunotherapy, it is critical to understand why some of the tumor cells escape from this immune attack. In this study, we investigated how HCC cells alter endogenous anti-tumor immunity and their related signaling pathways. We found that HCC cells, both in vitro and in vivo, substantially secret and express amphiregulin (AR). AR in turn activates immunosuppressive function of intratumoral CD4+Foxp3+ regulatory T cells (Tregs), a major inhibitor of CD8+ T cells. Using either lentiviral siRNA, or AR neutralizing antibody, we blocked the expression and function of AR to test the specificity of AR mediated activation of Tregs, Biochemical and cell biology studies were followed and confirmed that blocking of AR inhibited Tregs activation. In addition, we found that AR can trigger the activation of rapamycin complex 1(mTORC1) signaling in Tregs. The mTORC1 inhibitor rapamycin treatment led to compromise Treg function and resulted in enhancing anti-tumor function of CD8+ T cells. Blocking AR/EGFR signaling in Tregs with Gefitinib also enhanced anti-tumor immunity and decreased tumor size in a mouse xenograft tumor model. Taken together, our study suggested a novel mechanism of functional interaction between HCC and Tregs for regulating anti-tumor function of CD8+ T cells.
Highlights
Hepatocellular carcinoma (HCC) is the 3rd most common cause of cancer-related death worldwide
Previous observations have demonstrated the function of Tregs in inhibiting anti-tumor CD8+ T cells in HCC [6,7,8,9], the underlying cellular and molecular mechanisms concerning the activation of Tregs still remain largely unknown
We found that AR expression in the xenografts remains high as determined by Western blotting and Enzyme linked immunosorbent assay (ELISA) (Figure 1D, 1E)
Summary
Hepatocellular carcinoma (HCC) is the 3rd most common cause of cancer-related death worldwide. Spontaneous immune responses including T-cell responses [1] and humoral responses to different tumor-associated antigens [2] have been suggested to inhibit the tumor growth of HCC. Not all T cells are anti-tumor effector immune cells. Previous observations have demonstrated the function of Tregs in inhibiting anti-tumor CD8+ T cells in HCC [6,7,8,9], the underlying cellular and molecular mechanisms concerning the activation of Tregs still remain largely unknown. Most of the previous studies focused on either how Tregs suppress tumor-associated antigen (TAA) specific effector T cell function, or how Tregs regulate tumor-associated inflammation. The cellular and molecular mechanisms underlying the modulation of Tregs activity has been overlooked
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