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Although viral hepatocellular carcinoma (HCC) is declining, nonviral HCC, which often is the end stage of nonalcoholic or alcoholic steatohepatitis (NASH, ASH), is on an upward trajectory. Immune checkpoint inhibitors (ICIs) that block the T cell inhibitory receptor PD-1 were approved for treatment of all HCC types. However, only a minority of HCC patients show a robust and sustained response to PD-1 blockade, calling for improved understanding of factors that negatively impact response rate and duration and the discovery of new adjuvant treatments that enhance ICI responsiveness. Using a mouse model of NASH-driven HCC, we identified peritumoral fibrosis as a potential obstacle to T cell-mediated tumor regression and postulated that antifibrotic medications may increase ICI responsiveness. We now show that the angiotensin II receptor inhibitor losartan, a commonly prescribed and safe antihypertensive drug, reduced liver and peritumoral fibrosis and substantially enhanced anti-PD-1-induced tumor regression. Although losartan did not potentiate T cell reinvigoration, it substantially enhanced HCC infiltration by effector CD8⁺ T cells compared to PD-1 blockade alone. The beneficial effects of losartan correlated with blunted TGF-β receptor signaling, reduced collagen deposition, and depletion of immunosuppressive fibroblasts.

Collectively, these observations suggest that IKKbeta/NF-kappaB activation controls the development of liver metastasis by way of IL-6 expression and is a potential target for the development of antimetastatic drugs.

<div>Abstract<p>Murine liver tumors often fail to recapitulate the complexity of human hepatocellular carcinoma (HCC), which might explain the difficulty to translate preclinical mouse studies into clinical science. The aim of this study was to evaluate a subtyping approach for murine liver cancer models with regard to etiology-defined categories of human HCC, comparing genomic changes, histomorphology, and IHC profiles. Sequencing and analysis of gene copy-number changes [by comparative genomic hybridization (CGH)] in comparison with etiology-dependent subsets of HCC patients of The Cancer Genome Atlas (TCGA) database were conducted using specimens (75 tumors) of five different HCC mouse models: diethylnitrosamine (DEN) treated wild-type C57BL/6 mice, c-Myc and AlbLTαβ transgenic mice as well as TAK1<sup>LPC-KO</sup> and Mcl-1<sup>Δhep</sup> mice. Digital microscopy was used for the assessment of morphology and IHC of liver cell markers (A6-CK7/19, glutamine synthetase) in mouse and <i>n</i> = 61 human liver tumors. Tumor CGH profiles of DEN-treated mice and c-Myc transgenic mice matched alcohol-induced HCC, including morphologic findings (abundant inclusion bodies, fatty change) in the DEN model. Tumors from AlbLTαβ transgenic mice and TAK1<sup>LPC-KO</sup> models revealed the highest overlap with NASH-HCC CGH profiles. Concordant morphology (steatosis, lymphocyte infiltration, intratumor heterogeneity) was found in AlbLTαβ murine livers. CGH profiles from the Mcl-1<sup>Δhep</sup> model displayed similarities with hepatitis-induced HCC and characteristic human-like phenotypes (fatty change, intertumor and intratumor heterogeneity).</p>Implications:<p>Our findings demonstrate that stratifying preclinical mouse models along etiology-oriented genotypes and human-like phenotypes is feasible. This closer resemblance of preclinical models is expected to better recapitulate HCC subgroups and thus increase their informative value.</p></div>

Primary health-care providers have been encouraged to counsel their patients about regular physical activity, but there are significant barriers to effective counseling. In this study a program of training and materials was tested for acceptability to providers, office staff, and patients. Primary care providers and office staff were trained to use the Physician-based Assessment and Counseling for Exercise (PACE) materials in four geographical sites in the United States. The program was tested in a variety of settings and with diverse patient populations. The acceptability of the program during a five-month study period was evaluated through structured interviews. The training was effective in preparing the providers to counsel, and the program was generally acceptable to providers, office staff, and patients. Counseling was provided in less than five minutes by 70% of providers, and most patients reported following the recommendations given. The PACE program assists providers in overcoming barriers to counseling patients about physical activity. The PACE program is potentially an important part of a national effort to enhance the adoption and maintenance of physical activity among adults.