Targeting monocyte-intrinsic enhancer reprogramming improves immunotherapy efficacy in hepatocellular carcinoma.

OBJECTIVE: Hepatocellular carcinoma (HCC), mostly developed in fibrotic/cirrhotic liver, exhibits relatively low responsiveness to immune checkpoint blockade (ICB) therapy. As myeloid-derived suppressor cell (MDSC) is pivotal for immunosuppression, we investigated its role and regulation in the fibrotic microenvironment with an aim of developing mechanism-based combination immunotherapy. DESIGN: Functional significance of MDSCs was evaluated by flow cytometry using two orthotopic HCC models in fibrotic liver setting via carbon tetrachloride or high-fat high-carbohydrate diet and verified by clinical specimens. Mechanistic studies were conducted in human hepatic stellate cell (HSC)-peripheral blood mononuclear cell culture systems and fibrotic-HCC patient-derived MDSCs. The efficacy of single or combined therapy with anti-programmed death-1-ligand-1 (anti-PD-L1) and a clinically trialled BET bromodomain inhibitor i-BET762 was determined. RESULTS: Accumulation of monocytic MDSCs (M-MDSCs), but not polymorphonuclear MDSCs, in fibrotic livers significantly correlated with reduced tumour-infiltrating lymphocytes (TILs) and increased tumorigenicity in both mouse models. In human HCCs, the tumour-surrounding fibrotic livers were markedly enriched with M-MDSC, with its surrogate marker CD33 significantly associated with aggressive tumour phenotypes and poor survival rates. Mechanistically, activated HSCs induced monocyte-intrinsic p38 MAPK signalling to trigger enhancer reprogramming for M-MDSC development and immunosuppression. Treatment with p38 MAPK inhibitor abrogated HSC-M-MDSC crosstalk to prevent HCC growth. Concomitant with patient-derived M-MDSC suppression by i-BET762, combined treatment with anti-PD-L1 synergistically enhanced TILs, resulting in tumour eradication and prolonged survival in the fibrotic-HCC mouse model. CONCLUSION: Our results signify how non-tumour-intrinsic properties in the desmoplastic microenvironment can be exploited to reinstate immunosurveillance, providing readily translatable combination strategies to empower HCC immunotherapy.

Rates and risk factors associated with the progression of HIV to AIDS among HIV patients from Zhejiang, China between 2008 and 2012.

OBJECTIVES: The objective of this study was to determine the rate of acquired immune deficiency syndrome (AIDS) in Zhejiang province and to identify specific factors associated with progression of this disease. METHODS: This study utilized a retrospective cohort to identify the specific factors involved in the progression of human immunodeficiency virus (HIV) to AIDS. We collected data of patients existing in care between 2008 and 2012 from the national surveillance system databases. We performed our analyses using a multivariate Cox proportional hazards model. RESULTS: This study included 9216 HIV-positive patients (75.6 % male), which yielded 12,452 person-years (py) of follow-up-data. The AIDS progression rates were 33.9 % (2008), 33.6 % (2009), 38.1 % (2010), 30.6 % (2011) and 25.9 % (2012). We observed a significant reduction in the rate of progression Of HIV to AIDS post-2010 (Pearson χ(2) = 4341.9, P < 0.001). The cumulative AIDS progression incidence rates were 33.4, 35.4, 36.4, 37.0 and 37.04 per 100 py in 1 each of the 5 years of follow-up. This study found that age was an independent risk factor for the progression of HIV to AIDS. Compared with patients infected with HIV by homosexual transmission, patients infected with HIV by heterosexuals transmission or blood transfusion had a reduced hazard ratio (HR) for progression to AIDS (heterosexual transmission: HR = 0.695, 0.524, P = 0.007; blood transfusion: HR = 0.524, P = 0.015). Diagnosed with HIV from 2011 to 2012 and having a higher CD4+ cell count (350-500 cells/mm(3); or >500 cells/mm(3)) at baseline were independently associated with lower rates of HIV progression to AIDS [HR = 0.382, 0.380, 0.187, P < 0.001]. Patients with a CD+ T-cell count of 200-350 cells/mm(3) or greater than 350 cells/mm(3) were less likely to develop AIDS following HIV diagnosis than were those patients without HAART treatment. CONCLUSION: This study found a high progression rate from HIV to AIDS in HIV patients residing within Zhejiang province from 2008 to 2010. This rate decreased after 2010, which coincided with the new criteria for HAART treatment, which likely contributed to the observed reduction in the rate of progression. Initiation of HAART with higher CD4+ T-cell count may reduce rate of AIDS progression. Based on our results, we conclude that efficient strategies for HIV screening, as well as early diagnosis and treatment are necessary to reduce the progression of HIV to AIDS.

Aberrant cholesterol metabolic signaling impairs antitumor immunosurveillance through natural killer T cell dysfunction in obese liver.

Obesity is a major risk factor for cancers including hepatocellular carcinoma (HCC) that develops from a background of non-alcoholic fatty liver disease (NAFLD). Hypercholesterolemia is a common comorbidity of obesity. Although cholesterol biosynthesis mainly occurs in the liver, its role in HCC development of obese people remains obscure. Using high-fat high-carbohydrate diet-associated orthotopic and spontaneous NAFLD-HCC mouse models, we found that hepatic cholesterol accumulation in obesity selectively suppressed natural killer T (NKT) cell-mediated antitumor immunosurveillance. Transcriptome analysis of human liver revealed aberrant cholesterol metabolism and NKT cell dysfunction in NAFLD patients. Notably, cholesterol-lowering rosuvastatin restored NKT expansion and cytotoxicity to prevent obesogenic diet-promoted HCC development. Moreover, suppression of hepatic cholesterol biosynthesis by a mammalian target of rapamycin (mTOR) inhibitor vistusertib preceded tumor regression, which was abolished by NKT inactivation but not CD8+ T cell depletion. Mechanistically, sterol regulatory element-binding protein 2 (SREBP2)-driven excessive cholesterol production from hepatocytes induced lipid peroxide accumulation and deficient cytotoxicity in NKT cells, which were supported by findings in people with obesity, NAFLD and NAFLD-HCC. This study highlights mTORC1/SREBP2/cholesterol-mediated NKT dysfunction in the tumor-promoting NAFLD liver microenvironment, providing intervention strategies that invigorating NKT cells to control HCC in the obesity epidemic.

Cell cycle-related kinase reprograms the liver immune microenvironment to promote cancer metastasis.

The liver is an immunologically tolerant organ and a common metastatic site of multiple cancer types. Although a role for cancer cell invasion programs has been well characterized, whether and how liver-intrinsic factors drive metastatic spread is incompletely understood. Here, we show that aberrantly activated hepatocyte-intrinsic cell cycle-related kinase (CCRK) signaling in chronic liver diseases is critical for cancer metastasis by reprogramming an immunosuppressive microenvironment. Using an inducible liver-specific transgenic model, we found that CCRK overexpression dramatically increased both B16F10 melanoma and MC38 colorectal cancer (CRC) metastasis to the liver, which was highly infiltrated by polymorphonuclear-myeloid-derived suppressor cells (PMN-MDSCs) and lacking natural killer T (NKT) cells. Depletion of PMN-MDSCs in CCRK transgenic mice restored NKT cell levels and their interferon gamma production and reduced liver metastasis to 2.7% and 0.7% (metastatic tumor weights) in the melanoma and CRC models, respectively. Mechanistically, CCRK activated nuclear factor-kappa B (NF-κB) signaling to increase the PMN-MDSC-trafficking chemokine C-X-C motif ligand 1 (CXCL1), which was positively correlated with liver-infiltrating PMN-MDSC levels in CCRK transgenic mice. Accordingly, CRC liver metastasis patients exhibited hyperactivation of hepatic CCRK/NF-κB/CXCL1 signaling, which was associated with accumulation of PMN-MDSCs and paucity of NKT cells compared to healthy liver transplantation donors. In summary, this study demonstrates that immunosuppressive reprogramming by hepatic CCRK signaling undermines antimetastatic immunosurveillance. Our findings offer new mechanistic insights and therapeutic targets for liver metastasis intervention.