Regulatory T cells with multiple suppressive and potentially pro-tumor activities accumulate in human colorectal cancer

Tregs can contribute to tumor progression by suppressing antitumor immunity. Exceptionally, in human colorectal cancer (CRC), Tregs are thought to exert beneficial roles in controlling pro-tumor chronic inflammation. The goal of our study was to characterize CRC-infiltrating Tregs at multiple levels, by phenotypical, molecular and functional evaluation of Tregs from the tumor site, compared to non-tumoral mucosa and peripheral blood of CRC patients. The frequency of Tregs was higher in mucosa than in blood, and further significantly increased in tumor. Ex vivo, those Tregs suppressed the proliferation of tumor-infiltrating CD8+ and CD4+ T cells. A differential compartmentalization was detected between Helioshigh and Helioslow Treg subsets (thymus-derived versus peripherally induced): while Helioslow Tregs were enriched in both sites, only Helioshigh Tregs accumulated significantly and specifically in tumors, displayed a highly demethylated TSDR region and contained high proportions of cells expressing CD39 and OX40, markers of activation and suppression. Besides the suppression of T cells, Tregs may contribute to CRC progression also through releasing IL-17, or differentiating into Tfr cells that potentially antagonize a protective Tfh response, events that were both detected in tumor-associated Tregs. Overall, our data indicate that Treg accumulation may contribute through multiple mechanisms to CRC establishment and progression

Chronic hepatitis B virus and hepatitis C virus infections and cancer: Synergy between viral and host factors

Hepatitis B virus (HBV) or hepatitis C virus (HCV) infections represent major causes of chronic liver disease and hepatocellular carcinoma. Despite inducing shared pathological events leading to oncogenic transformation, these two viruses present profound differences in their molecular features, life cycle and interplay with host factors, which signi fi cantly differentiate the prognostic and therapeutic approach to the related diseases. In the present review, we report the main mechanisms involved in the multistep process leading from HCV/HBV infection and cancer development, discussing side-by-side the analogies and differences between the two viruses. Such events can be broadly categorized into (a) direct oncogenic effects, involving integration in the host genome (in the case of HBV) and chromosomal instability, interference with oncosuppressor pathways, induction of oxidative stress, promotion of angiogenesis, epithelial – mesenchymal transition, alterations in the epigenetic asset and interaction with non-coding RNAs; and (b) indirect activities mostly mediated by host events, including chronic in fl ammation sustained by peculiar cytokine networks (such as interleukin-6 and lymphotoxins), metabolic dysfunctions promoted by steatohepatitis, interplay with gut microbiota and fi brotic events (mainly in HCV infection). This scenario suggests that the integrated study of viral and host factors may lead to the successful development of novel biomarkers and targets f

hSirT1-Dependent Regulation of the PCAF-E2F1-p73 Apoptotic Pathway in Response to DNA Damage▿

The NAD+-dependent histone deacetylase hSirT1 regulates cell survival and stress responses by inhibiting p53-, NF-κB-, and E2F1-dependent transcription. Here we show that the hSirT1/PCAF interaction controls the E2F1/p73 apoptotic pathway. hSirT1 represses E2F1-dependent P1p73 promoter activity in untreated cells and inhibits its activation in response to DNA damage. hSirT1, PCAF, and E2F1 are corecruited in vivo on theP1p73 promoter. hSirT1 deacetylates PCAF in vitro and modulates PCAF acetylation in vivo. In cells exposed to apoptotic DNA damage, nuclear NAD+ levels decrease and inactivate hSirT1 without altering the hSirT1 interaction with PCAF and hSirT1 binding to the P1p73 promoter. The reactivation of hSirT1 by pyruvate that increases the [NAD+]/[NADH] ratio completely abolished the DNA damage-induced activation of TAp73 expression, thus linking the modulation of chromatin-bound hSirT1 deacetylase activity by the intracellular redox state with P1p73 promoter activity. The release of PCAF from hSirT1 repression favors the assembly of transcriptionally active PCAF/E2F1 complexes onto the P1p73 promoter and p53-independent apoptosis. Our results identify hSirT1 and PCAF as potential targets to modulate tumor cell survival and chemoresistance irrespective of p53 status

Wnt3a/b-Catenin signaling conditions differentiation of partially exhausted T-effector cells in human cancers

In this study, we investigated the role of the Wnt/b-catenin signaling pathway in antitumor immune responses. We report that the concentration of secreted Wnt3a was significantly higher in conditioned medium from tumor or nontumor tissues obtained from all hepatocellular carcinoma or colorectal cancer patients tested, than in serum of healthy donors or patients. In addition, both Wnt3a and b-catenin were overexpressed by tumor-infiltrating and nontumor-infiltrating CD4\ufe or CD8\ufe T cells. The majority of these T cells expressed a dysfunctional effector memory Eomes\ufeT-betphenotype that we defined as partially exhausted, because they performed effector functions (in terms of interferon-g and tumor necrosis factor-a production, as well as CD107a mobilization) despite their PD-1 expression. Wnt3a/b-catenin signaling in T na\uefve cells in vitro recapitulated the T-cell setting in vivo. Indeed, the differentiation of cultured T na\uefve cells was arrested, producing cells that resembled the EomeshighT-betlowb-cateninhigh T cells with moderate effector functions that infiltrated tumor and nontumor areas. Wnt3a blockade improved the capacity of T na\uefve cells to differentiate into effector cells in vitro. However, Wnt3a blockade did not affect the function and phenotype of differentiated, partially exhausted, tumor-infiltrating T cells ex vivo. Taken together, our data suggest that Wnt3a blockade halts the capacity of Wnt/b-catenin signaling to inhibit the differentiation of T na\uefve cells, but it does not restore the dysfunction of differentiated T cells, in the tumor setting