Loss of immunity-supported senescence enhances susceptibility to hepatocellular carcinogenesis and progression in Toll-like receptor 2-deficient mice

Abstract

Hepatocellular carcinoma (HCC) is a complication at the endstage of chronic inflammatory liver diseases with dismal prognosis. Targeting of Toll-like receptor (TLR) 2 attenuates tumor metastases; we hypothesized that blocking TLR2 might also play a crucial role in reducing hepatocarcinogenesis. Surprisingly, we found that the genetic deletion of TLR2 increased susceptibility to diethylnitrosamine (DEN), a genotoxic carcinogen that can induce HCC. Indeed, TLR2-deficient mice showed a significant increase in carcinogenesis and progression of HCC as indicated by increases in tumor nodule size, tumor volume, and animal death. The enhanced susceptibility to DEN-induced HCC was associated with a broad-spectrum reduction in the immune response to DEN-induced liver injury. We found that TLR2 deficiency caused a decrease in the infiltration of macrophages and an attenuation of apoptosis signal regulating kinase 1 (ASK1) / p38 mitogen-activated protein kinase (p38 MAPK) / nuclear factor kappa B (NF-jB) signaling, which led to a decrease in the expression of interferon-gamma (IFN-c), tumor necrosis factor alpha (TNF-a), interleukin (IL)-1a/b, IL-6, and Cxcl-2 as well as suppression of autophagy flux and increases in oxidative stress and p62 aggregation in liver tissue. The defects in immune networks resulted in suppressed p21-and p16/pRb-dependent senescence, which caused an increase in proliferation and a decrease in apoptotic and autophagy-associated cell death in mouse livers. Restoring cellular senescence and autophagy flux by treating TLR2-deficient mice with IFN-c, a T helper 1 (Th1) cytokine and positive modulator of senescence and autophagy, could attenuate the carcinogenesis and progression of HCC associated with TLR2-deficient animals. Conclusion: The loss of immune networks supporting cellular senescence and autophagy flux is attributed to enhanced susceptibility to DEN-induced hepatocellular carcinogenesis and progression in TLR2-deficient mice. These findings may be used to prevent the development of liver cancer. (HEPATOLOGY 2013;57:171-182)

Efficient Induction of Antitumor Immunity by Synthetic Toll-like Receptor Ligand–Peptide Conjugates

“…The combinatory effect of integrated CD8 þ and CD4 þ T-cell response induction, together with the strong TLR signaling, thus constitutes a highly efficient vaccination format. Triggering of TLRs has been implicated in both beneficial and detrimental effects in antitumor immunity, with the detrimental effects mostly being inflicted by direct interactions of TLR-Ls with TLRs expressed on tumor cells (29)(30)(31). We and others have observed strong immune-potentiating effects of TLR2 triggering (16,32) as well as its effects in tumor eradication (14,33).…”

NK cell receptor imbalance and NK cell dysfunction in HBV infection and hepatocellular carcinoma

“…Survival analysis also showed that higher sMICA levels were related with poor prognosis in HCC patients, and sMICA is regarded as a predictive biomarker for HBV-induced HCC. 96,97 Significantly higher levels of sMICA/B were also observed in patients with chronic liver disease compared with healthy volunteers. 98 Reduced expression of another NKG2D ligand, ULBP1, has also been observed in HCC, and soluble ULBP1 prevented effective NKG2D-mediated killing and led to early recurrence of HCC after hepatectomy.…”

“…NKG2D, an activating receptor whose ligands include MICA, MICB and the ULBPs, has a crucial role in NK cell activation. Although NKG2D ligands are usually upregulated on a wide range of tumor cells due to cellular stress during malignant 66,95,96 Serum sMICA was studied in 26 patients with HCC and significant amounts of sMICA were detected in 11 of the patients, while no sMICA was detected in chronic HBV/HCV patients or healthy controls except for five cases with marginal positivity. More importantly, the percentage of sMICA-positive patients is higher among advanced HCC patients (stage III or IV) than in stage I or II patients (71% versus 8.4%).…”

Autophagy-mediated regulation of macrophages and its applications for cancer

“…Indeed, TLR2 deficiency induces a significant reduction of autophagy and macrophage infiltration in liver tissues, and promotes hepatocarcinogenesis, suggesting a potential role of TLR2 in tumorigenesis by modulation of autophagy in macrophages. 74 Future studies should aim at using genetic approaches that specifically inhibit or facilitate autophagy in macrophages or their precursors, thus helping to establish in detail the roles of autophagy in regulating macrophage production, tumor growth, and progression in vivo.…”

“…For example, even if TLR2 deficiency causes a reduction of macrophage infiltration, this ablation also induces a significant suppression of autophagy and a reduction in the expression of TNF/ TNFα (tumor necrosis factor), IFNG (interferon, gamma) and CXCL2 (chemokine [C-X-C motif] ligand 2) in liver tissues, indicating an increase of M2 macrophage polarization, which in turn promotes hepatocarcinogenesis. 74 Notably, recent findings highlight that activation of the MTOR-TSC2 pathway, a key regulator of autophagy, is critical for macrophage polarization toward the M2 phenotype to promote tumor angiogenesis and growth in mouse hepatocellular carcinoma models, whereas inhibition of this pathway exerts the opposite effects. 66 Thus, the polarization of macrophages regulated by autophagy may represent a promising and effective strategy for liver cancer therapies.…”