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Significance T cells recognize their targets via their T-cell receptors (TCRs), which in the case of CD8+ T cells bind to MHC-I:antigen complexes on the surface of target cells. Many cancer cells evade immune recognition and killing by down-regulating MHC-I AgPPM. Here, we show how the histone acetyl transferases p300/CBP together with NF-κB epigenetically regulate expression of MHC-I molecules, immunoproteasome subunits, and peptide transporter to enable proper MHC-I antigen presentation. Notably, this pathway is frequently disrupted in human cancers. We now show that certain chemotherapeutics can augment MHC-I antigen presentation via NF-κB and p300/CBP activation, thereby enhancing cancer cell recognition and killing by effector CD8+ CTLs., Many cancers evade immune rejection by suppressing major histocompatibility class I (MHC-I) antigen processing and presentation (AgPP). Such cancers do not respond to immune checkpoint inhibitor therapies (ICIT) such as PD-1/PD-L1 [PD-(L)1] blockade. Certain chemotherapeutic drugs augment tumor control by PD-(L)1 inhibitors through potentiation of T-cell priming but whether and how chemotherapy enhances MHC-I–dependent cancer cell recognition by cytotoxic T cells (CTLs) is not entirely clear. We now show that the lysine acetyl transferases p300/CREB binding protein (CBP) control MHC-I AgPPM expression and neoantigen amounts in human cancers. Moreover, we found that two distinct DNA damaging drugs, the platinoid oxaliplatin and the topoisomerase inhibitor mitoxantrone, strongly up-regulate MHC-I AgPP in a manner dependent on activation of nuclear factor kappa B (NF-κB), p300/CBP, and other transcription factors, but independently of autocrine IFNγ signaling. Accordingly, NF-κB and p300 ablations prevent chemotherapy-induced MHC-I AgPP and abrogate rejection of low MHC-I–expressing tumors by reinvigorated CD8+ CTLs. Drugs like oxaliplatin and mitoxantrone may be used to overcome resistance to PD-(L)1 inhibitors in tumors that had “epigenetically down-regulated,” but had not permanently lost MHC-I AgPP activity.

In this Article, the sentence: "After 7 months of HFD, MUP-uPA mice developed HCC15, which contained numerous (usually 50-100 per tumour) non-recurrent coding mutations in pathways that are mutated in human HCC (Fig. 2d and Extended Data Fig. 6a).", should have read: "After 7 months of HFD, MUP-uPA mice developed HCC15, which contained numerous (usually 50-100 per tumour) non-recurrent mutations in pathways that are mutated in human HCC (Fig. 2d and Extended Data Fig. 6a).". This has been corrected online. In Extended Data Fig. 6a and b, which show the number of point mutations identified per sample and the mutational signatures, all sequence variants (including non-coding mutations) are shown. Fig. 2d also presents all variants compared to human mutations. In the Supplementary Information to this Amendment, we now provide the comparisons of all variants and coding variants to human mutations.

Dysregulated NLRP3 inflammasome activity results in uncontrolled inflammation, which underlies many chronic diseases. Although mitochondrial damage is needed for the assembly and activation of the NLRP3 inflammasome, it is unclear how macrophages are able to respond to structurally diverse inflammasome-activating stimuli. Here we show that the synthesis of mitochondrial DNA (mtDNA), induced after the engagement of Toll-like receptors, is crucial for NLRP3 signalling. Toll-like receptors signal via the MyD88 and TRIF adaptors to trigger IRF1-dependent transcription of CMPK2, a rate-limiting enzyme that supplies deoxyribonucleotides for mtDNA synthesis. CMPK2-dependent mtDNA synthesis is necessary for the production of oxidized mtDNA fragments after exposure to NLRP3 activators. Cytosolic oxidized mtDNA associates with the NLRP3 inflammasome complex and is required for its activation. The dependence on CMPK2 catalytic activity provides opportunities for more effective control of NLRP3 inflammasome-associated diseases.

Summary Background The ability of circulating microRNAs (miRNAs) to detect preclinical hepatocellular carcinoma has not yet been reported. We aimed to identify and assess a serum miRNA combination that could detect the presence of clinical and preclinical hepatocellular carcinoma in at-risk patients. Methods We did a three-stage study that included healthy controls, inactive HBsAg carriers, individuals with chronic hepatitis B, individuals with hepatitis B-induced liver cirrhosis, and patients with diagnosed hepatocellular carcinoma from four hospitals in China. We used array analysis and quantitative PCR to identify 19 candidate serum miRNAs that were increased in six patients with hepatocellular carcinoma compared with eight control patients with chronic hepatitis B. Using a training cohort of patients with hepatocellular carcinoma and controls, we built a serum miRNA classifier to detect hepatocellular carcinoma. We then validated the classifiers' ability in two independent cohorts of patients and controls. We also established the classifiers' ability to predict preclinical hepatocellular carcinoma in a nested case-control study with sera prospectively collected from patients with hepatocellular carcinoma before clinical diagnosis and from matched individuals with hepatitis B who did not develop cancer from the same surveillance programme. We used the sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) to evaluate diagnostic performance, and compared the miRNA classifier with α-fetoprotein at a cutoff of 20 ng/mL (AFP20). Findings Between Aug 1, 2009, and Aug 31, 2013, we recruited 257 participants to the training cohort, and 352 and 139 participants to the two independent validation cohorts. In the third validation cohort, 27 patients with hepatocellular carcinoma and 135 matched controls were included in the nested case-control study, which ran from Aug 1, 2009, to Aug 31, 2014. We identified a miRNA classifier (C mi ) containing seven differentially expressed miRNAs (miR-29a, miR-29c, miR-133a, miR-143, miR-145, miR-192, and miR-505) that could detect hepatocellular carcinoma. C mi showed higher accuracy than AFP20 to distinguish individuals with hepatocellular carcinoma from controls in the validation cohorts, but not in the training cohort (AUC 0·826 [95% CI 0·771–0·880] vs 0·814 [0·756–0·872], p=0·72 in the training cohort; 0·817 [0·769–0·865] vs 0·709 [0·653–0·765], p=0·00076 in validation cohort 1; and 0·884 [0·818–0·951] vs 0·796 [0·706–0·886], p=0·042 for validation cohort 2). In all four cohorts, C mi had higher sensitivity (range 70·4–85·7%) than did AFP20 (40·7–69·4%) to detect hepatocellular carcinoma at the time of diagnosis, whereas its specificity (80·0–91·1%) was similar to that of AFP20 (84·9–100%). In the nested case-control study, sensitivity of C mi to detect hepatocellular carcinoma was 29·6% (eight of 27 cases) 12 months before clinical diagnosis, 48·1% (n=13) 9 months before clinical diagnosis, 48·1% (n=13) 6 months before clinical diagnosis, and 55·6% (n=15) 3 months before clinical diagnosis, whereas sensitivity of AFP20 was only 7·4% (n=2), 11·1% (n=3), 18·5% (n=5), and 22·2% (n=6) at the corresponding timepoints (p=0·036, p=0·0030, p=0·021, p=0·012, respectively). C mi had a larger AUC than did AFP20 to identify small-size (AUC 0·833 [0·782–0·883] vs 0·727 [0·664–0·792], p=0·0018) and early-stage (AUC 0·824 [0·781–0·868] vs 0·754 [0·702–0·806], p=0·015) hepatocellular carcinoma and could also detect α-fetoprotein-negative (AUC 0·825 [0·779–0·871]) hepatocellular carcinoma. Interpretation C mi is a potential biomarker for hepatocellular carcinoma, and can identify small-size, early-stage, and α-fetoprotein-negative hepatocellular carcinoma in patients at risk. The miRNA classifier could be valuable to detect preclinical hepatocellular carcinoma, providing patients with a chance of curative resection and longer survival. Funding National Key Basic Research Program, National Science and Technology Major Project, National Natural Science Foundation of China.

Nature 551, 340–345 (2017); doi:10.1038/nature24302 In this Article, owing to an error during the production process, the text ‘(Iga is also known as Cd79a)’ was erroneously added to the sentence describing the generation of MUP-uPA/Iga−/− and STAM/Iga−/− mice; this should have stated ‘(Iga is also known as Igha)’.

The role of adaptive immunity in early cancer development is controversial. Here we show that chronic inflammation and fibrosis in humans and mice with non-alcoholic fatty liver disease is accompanied by accumulation of liver-resident immunoglobulin-A-producing (IgA+) cells. These cells also express programmed death ligand 1 (PD-L1) and interleukin-10, and directly suppress liver cytotoxic CD8+ T lymphocytes, which prevent emergence of hepatocellular carcinoma and express a limited repertoire of T-cell receptors against tumour-associated antigens. Whereas CD8+ T-cell ablation accelerates hepatocellular carcinoma, genetic or pharmacological interference with IgA+ cell generation attenuates liver carcinogenesis and induces cytotoxic T-lymphocyte-mediated regression of established hepatocellular carcinoma. These findings establish the importance of inflammation-induced suppression of cytotoxic CD8+ T-lymphocyte activation as a tumour-promoting mechanism.

miR-122 is a highly abundant, hepatocyte-specific microRNA. The biomedical significance and regulatory mechanisms of miR-122 remain obscure. We explored the role of miR-122 in tumorigenesis in the context of gene regulatory network. The miR-122 promoter and its transactivator were identified by way of luciferase reporter system, electrophoretic mobility shift, and chromatin immunoprecipitation assays. The miR-122 regulatory circuitry and its implication in hepatocarcinogenesis were identified using livers of different development stages, human hepatocellular carcinoma (HCC) tissues and cell lines, and aflatoxin B1 (AFB1)-transformed cells. We characterized the −5.3 to −4.8 kb region upstream of miR-122 precursor as miR-122 promoter. Further investigation revealed that deletion of predicted CCAAT/enhancer-binding protein alpha (C/EBPα) binding sites C/EBPα knockdown significantly reduced miR-122 promoter activity and endogenous miR-122 expression; and C/EBPα directly interacted with the miR-122 promoter in vitro and in vivo. These data suggest that C/EBPα is a transactivator for miR-122 transcription. We further demonstrated that miR-122 suppressed insulin-like growth factor 1 receptor (IGF-1R) translation and sustained glycogen synthase kinase-3 beta (GSK-3β) activity. The activated GSK-3β not only repressed cell proliferation, but also activated C/EBPα, which maintained miR-122 levels and thereby enforced IGF-1R suppression. Interestingly, down-regulation of miR-122 and C/EBPα, and up-regulation of IGF-1R were frequently observed in HCC tissues, and decreased miR-122 levels were associated with worse survival of HCC patients. Moreover, AFB1 exposure resulted in decreased activity in GSK-3β, C/EBPα, and miR-122 and increased levels of IGF-1R, whereas restoration of miR-122 suppressed the tumorigenicity of HCC and AFB1-transformed cells. Conclusion: We have identified a novel GSK-3β–C/EBPα–miR-122–IGF-1R regulatory circuitry whose dysfunction may contribute to the development of HCC. Our findings provide new insight into miR-122's function and the mechanisms of hepatocarcinogenesis. (Hepatology 2010;52:1702-1712)