Hepatocellular carcinoma (HCC) is a frequent cancer with limited treatment options and poor prognosis. Tumorigenesis has been linked with macrophage-mediated chronic inflammation and diverse signaling pathways including the Epidermal Growth Factor Receptor (EGFR) pathway. The precise role of EGFR in HCC is unknown, and EGFR-inhibitors have shown disappointing clinical results. Here we discover that EGFR is expressed in liver macrophages in both human HCC and in a mouse HCC model. Mice lacking EGFR in macrophages show impaired hepatocarcinogenesis, whereas mice lacking EGFR in hepatocytes unexpectedly develop more HCC due to increased hepatocyte damage and compensatory proliferation. Mechanistically, following IL-1 stimulation, EGFR is required in liver macrophages to transcriptionally induce IL-6, which triggers hepatocyte proliferation and HCC. Importantly, the presence of EGFR-positive liver macrophages in HCC-patients is associated with poor survival. This study demonstrates a tumor-promoting mechanism for EGFR in non-tumor cells, which could lead to more effective precision medicine strategies.

Mouse and human genomes carry more than a dozen genes coding for closely related alpha interferon (IFN-␣) subtypes. IFN-␣, as well as IFN-␤, IFN-, IFN-, and limitin, are thought to bind the same receptor, raising the question of whether different IFN subtypes possess specific functions. As some confusion existed in the identity and characteristics of mouse IFN-␣ subtypes, the availability of data from the mouse genome sequence prompted us to characterize the murine IFN-␣ family. A total of 14 IFN-␣ genes were detected in the mouse genome, in addition to three IFN-␣ pseudogenes. Four IFN-␣ genes (IFN-␣1, IFN-␣7/10, IFN-␣8/6, and IFN-␣11) exhibited surprising allelic divergence between 129/Sv and C57BL/6 mice. All IFN-␣ subtypes were found to be stable at pH 2 and to exhibit antiviral activity. Interestingly, some IFN subtypes (IFN-␣4, IFN-␣11, IFN-␣12, IFN-␤, and limitin) showed higher biological activity levels than others, whereas IFN-␣7/10 exhibited lower activity. Most murine IFN-␣ turned out to be N-glycosylated. However, no correlation was found between N-glycosylation and activity. The various IFN-␣ subtypes displayed a good correlation between their antiviral and antiproliferative potencies, suggesting that IFN-␣ subtypes did not diverge primarily to acquire specific biological activities but probably evolved to acquire specific expression patterns. In L929 cells, IFN genes activated in response to poly(I•C) transfection or to viral infection were, however, similar.

There is increasing evidence that the effect of chemotherapy on tumor growth is not cell autonomous but relies on the immune system. The objective of this study was therefore to decipher the cellular and molecular mechanisms underlying the role of innate and adaptive immunity in chemotherapy-induced tumor rejection. Treatment of DBA/2 mice bearing P815 mastocytoma with cyclophosphamide induced rejection and long-term protection in a CD4-and CD8-dependent manner. A population of inflammatory-type dendritic cells was dramatically expanded in the lymph nodes of mice that rejected the tumor and correlated with CD4-dependent infiltration, in tumor bed, of tumor-specific CD8 1 T lymphocytes. Our data point to a major role of CD4 1 T cells in inducing chemokine expression in the tumor, provoking migration of tumor-specific CXCR3 1 CD8 1 T lymphocytes. Importantly, the analysis of CD8 1 T cells specific to P1A/H-2L d and P1E/H-2K d revealed that cyclophosphamide altered the P815-specific CD8 T repertoire by amplifying the response specific to the mutated P1E antigen.Increasing evidence suggests that tumor infiltration by T lymphocytes is a good prognostic factor for cancer patients. The prognostic and predictive impact of the immune infiltrates has been demonstrated in colorectal, ovarian, breast cancers and melanomas.