Highlights d The PIDDosome controls hepatocyte ploidy during postnatal development & regeneration d The PIDDosome defines the speed of liver regeneration posthepatectomy d Aneuploidy in the liver correlates with basal ploidy state but is not limited by CASP2 d E2F family members regulate expression of CASP2 and PIDD1 for liver ploidy control

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Polyploidization frequently precedes tumorigenesis but also occurs during normal development in several tissues. Hepatocyte ploidy is controlled by the PIDDosome during development and regeneration. This multi-protein complex is activated by supernumerary centrosomes to induce p53 and restrict proliferation of polyploid cells, otherwise prone for chromosomal instability. PIDDosome deficiency in the liver results in drastically increased polyploidy. To investigate PIDDosome-induced p53-activation in the pathogenesis of liver cancer, we chemically induced hepatocellular carcinoma (HCC) in mice. Strikingly, PIDDosome deficiency reduced tumor number and burden, despite the inability to activate p53 in polyploid cells. Liver tumors arise primarily from cells with low ploidy, indicating an intrinsic pro-tumorigenic effect of PIDDosome-mediated ploidy restriction. These data suggest that hyperpolyploidization caused by PIDDosome deficiency protects from HCC. Moreover, high tumor cell density, as a surrogate marker of low ploidy, predicts poor survival of HCC patients receiving liver transplantation. Together, we show that the PIDDosome is a potential therapeutic target to manipulate hepatocyte polyploidization for HCC prevention and that tumor cell density may serve as a novel prognostic marker for recurrence-free survival in HCC patients.

Key Points We describe a novel allo-tumor–reactive and CD8α-dependent Vγ5Vδ1TCR. The molecular interface with proximity to the peptide-binding groove of HLA-A*24:02 is an essential determinant of recognition.

The study of the immune response in several types of tumors has been rapidly increasing in recent years with the dual aim of understanding the relationship between neoplastic and immune cells as well as identifying targets for cancer immunotherapy. Despite being considered one of the most immunogenic tumor types, melanoma can progress in the presence of abundant lymphocytic infiltration, therefore suggesting that the immune response is not able to efficiently control tumor growth. The purpose of this study was to investigate whether the density, distribution and grade of tumor-infiltrating lymphocytes (TILs) in 97 canine melanocytic tumors is associated with histologic indicators of malignancy and can be considered a prognostic factor in the dog. As a further step in the characterization of the immune response in melanocytic tumors, an immunohistochemical investigation was performed to evaluate the two main populations of TILs, T-lymphocytes (CD3 +) and B-lymphocytes (CD20 +). The results of our study show that TILs are present in a large proportion of canine melanocytic tumors, especially in oral melanomas, and that, differently from humans, the infiltrate is usually mild. The quantity of CD20 + TILs was significantly associated with some histologic prognostic factors, such as the mitotic count, the cellular pleomorphism and the percentage of pigmented cells. Remarkably, a high infiltration of CD20 + TILs was associated with tumor-related death, presence of metastasis/recurrence, shorter overall and disease-free survival, increased hazard of death and of developing recurrence/metastasis, hence representing a potential new negative prognostic factor in canine melanocytic tumors.