Biology subjects

Cogliati, B.

Publications and source records attributed to Cogliati, B..

7 recordsLinked to original sources

bioRxiv2026

B cells sustain tumor-specific CD4 T cells to promote response to PD-1 targeted therapy

Immunotherapy transformed cancer treatment, yet precise correlates of response remain to be defined. While intratumoral follicular helper like (Tfhl) CD4 T cells and IgG1+ B cells have been associated with improved outcomes to PD-1 blockade for hepatocellular carcinoma (HCC), their mechanisms contributing to response are unclear. To address this question, we developed a murine model of HCC and examined CD8, CD4 and B cell responses. Increasing CD4-help sensitizes mice to PD-1 blockade, in a CD4- and CD8-dependent manner. Tumor-specific CD4 T cells contained Tfhl and Th1 populations, and both Bcl6 and T-bet were required for efficacy. Antigen-specific B cells were essential for CD4-helper expansion, yet secretion of antibodies was not required for long-term survival. Thus, B cells are critical for effective immunotherapy, but secreted antibodies are not.

immunology↗

bioRxiv2026

A Paracrine Dietary Lipid Axis Constrains Antitumor Immunity in Liver Cancer

Overnutrition-related liver dysfunction and cancer are increasingly prevalent and highly resistant to immunotherapy. While metabolic dysregulation is a hallmark of hepatocellular carcinoma (HCC), how nutrient overload impairs antitumor immunity remains unclear. Here, we show that short-term Western diet (WD) exposure drives near-complete loss of CD8 T cell infiltration and antitumor function in HCC. We identify dietary linoleic acid (LA), the most abundant {omega}-6 fatty acid, as the dominant immunosuppressive driver. Cancer cell-restricted FADS2-mediated desaturation of LA to longer-chain {omega}-6 PUFAs drives their accumulation in the tumor interstitial fluid, suppressing infiltrating CD8 T cells via lipid peroxidation. FADS2 inhibition restores CD8 T cell function and sensitizes WD-driven HCC to PD-1-based immunotherapy. Further, the Parkinsons disease-associated deglycase DJ-1 protects LA-handling proteins from methylglyoxal-mediated glycation, sustaining tumoral immunosuppressive PUFA production. Across multiple independent human MASLD-HCC cohorts, LA metabolic activity correlates with CD8 T cell impairment, immune exclusion, and immunotherapy resistance. Overall, these studies identify a dietary lipid axis as a therapeutically actionable vulnerability in WD-associated HCC.

Cancer Biology↗

bioRxiv2025

Liver Zonation Disruption Fuels Hepatocellular Carcinoma in Chronic Liver Disease

Hepatocellular carcinoma (HCC) arises almost exclusively in chronic liver disease (CLD), yet the classical etiological drivers of injury insufficiently explain why only a subset of patients progress to cancer. Here, we identify disruption of liver metabolic zonation, specifically, aberrant expansion of {beta}-catenin activity from pericentral to periportal territories as a previously unrecognized tumorigenic risk state that emerges across etiologically diverse CLDs. Using spatial transcriptomics and immunohistochemistry from murine liver disease followed by human sample validation, we demonstrate that MASLD/MASH, alcohol-associated hepatitis, viral hepatitis, and immune-mediated cholangiopathies share a striking periportal induction of pericentral {beta}-catenin target programs, indicating a conserved zonation disturbance independent of disease etiology. Since {beta}-catenin expansion occurs alongside inflammation, fibrosis, and metabolic dysfunction in human CLD, its direct oncogenic contribution remained unclear. To functionally isolate the tumorigenic consequence of zonation disruption itself from these confounding disease processes, we employed hepatocyte-specific deletion of ZNRF3 and RNF43--negative regulators that physiologically restrict {beta}-catenin to the pericentral zone. Lineage tracing demonstrates that ZNRF3/RNF43 deletion drives selective periportal hepatocyte proliferation, zonal reprogramming, and tumor initiation in a {beta}-catenin-dependent manner, establishing zonation disruption as a direct mechanistic driver of carcinogenesis. The resulting tumors exhibit a distinct metabolic and immunologic phenotype, including heightened mitochondrial respiration, preserved periportal identity, and T-cell competence, and correspond to a molecularly defined subset comprising 5-10% of human HCCs. Together, these findings reveal {beta}-catenin zonation expansion as a conserved and previously unrecognized HCC risk factor that mechanistically links chronic liver injury to malignant transformation. They further establish ZNRF3/RNF43 deletion as a tractable model of zonation-driven hepatocarcinogenesis and identify a distinct human HCC subtype with unique therapeutic vulnerabilities, opening new avenues for mechanism-based risk stratification, early detection and preventive therapeutic strategies in patients with chronic liver disease.

cancer biology↗

bioRxiv2025

An immunocompetent murine model of virus-elicited liver fibrosis and hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the third deadliest cancer worldwide. Over 75% of HCC cases are associated with chronic viral infections. Mechanistic studies and preclinical therapeutic development for virus-associated HCC have been limited by a paucity of small animal models of chronic hepatotropic virus infection that faithfully recapitulate human disease. Here we demonstrate the induction of chronic hepatitis, progressive liver fibrosis, and HCC in immunocompetent laboratory mice upon chronic viral infection with Norway rat hepacivirus (NrHV) - a virus closely related to hepatitis C virus (HCV). NrHV-elicited tumors resemble HCV-associated tumors and liver transcriptome analyses reveal numerous similarities between chronic NrHV and HCV. These findings establish an experimentally tractable, physiologically relevant, and immunocompetent mouse model of virus-elicited progressive liver fibrosis and oncogenesis.

pathology↗

bioRxiv2025

Scar-associated endothelial-stellate cellular crosstalk drives fibrosis resolution in MASH

Fibrosis, or scarring, can affect many organs including liver, lung, heart, kidney, intestines etc. and is responsible for [~]40% of mortality in the industrialized world. Compared to other organs, fibrosis in the liver typically resolves when the source of injury is extinguished. Elucidating the molecular mechanisms that underlie spontaneous fibrosis resolution in the liver may lead to novel antifibrotic strategies for all organs. In this study we established a robust mouse model of fibrosis regression in MASH (Metabolic dysfunction-Associated Steatohepatitis), a highly prevalent chronic liver diseases worldwide, and performed single cell and in situ molecular profiling of the liver to define novel drivers of fibrosis regression. As fibrosis regressed, we detected a reduction of inflammatory cells and an expansion of endothelial cells. Prediction of cell-cell communication using the Calligraphy pipeline identified a Wnt9b-Sfrp2 crosstalk that emerges as fibrosis resolved in our model. To establish the Wnt9b-Sfrp2 crosstalk as a driver of fibrosis resolution we treated mice with recombinant Sfrp2, which slowed spontaneous fibrosis regression compared to vehicle treated mice. From our single cell datasets we identified a subset of endothelial cells, termed "Endo4", as the source of Wnt9b. Immunostaining of the Endo4 marker VWF using tissue clearing and 3D imaging revealed VWF+ vasculature enveloped by activated hepatic stellate cells (HSCs) that penetrated deep into the fibrotic septa, establishing Endo4 as de facto scar-associated endothelial cells and providing a structural basis of their cellular crosstalk with HSCs. Finally, using a recently developed in situ protease activity screen, prominent serine protease activity co-localized with both scar-associated Endo4 cells and HSCs. In summary, we uncovered an WNT-dependent endo-stellate crosstalk within the fibrotic niche as a novel regulatory node underlying murine MASH fibrosis regression, and a promising therapeutic target.

molecular biology↗

bioRxiv2025

Targeting ZNRF3 and RNF43 to Restore Regeneration and Reverse Metabolic Dysfunction-Associated Steatotic Liver Disease

Liver regeneration and hepatocyte metabolic identity are disrupted in metabolic dysfunction-associated steatotic liver disease (MASLD) and its advanced form, metabolic dysfunction-associated steatohepatitis (MASH), yet the mechanisms of restore liver regeneration and reprogram metabolism for disease reversal remains poorly understood. Here, we show that {beta}-Catenin activity progressively declines in hepatocytes during MASH in both humans and mice, coinciding with impaired regeneration and defective lipid clearance. Targeted deletion of the endogenous WNT pathway inhibitors ZNRF3 and RNF43 in hepatocytes after MASH onset reactivates {beta}-Catenin signaling, leading to robust regression of steatosis, inflammation, and fibrosis, and restoring regenerative capacity across multiple fatty liver disease models. Mechanistically, this therapeutic effect is driven by {beta}-Catenin-dependent induction of the alternative bile acid synthesis pathway without disrupting systemic lipid homeostasis. Importantly, both short-and long-term deletion of ZNRF3/RNF43 restores liver function without triggering tumorigenesis or hepatotoxicity, indicating a safe therapeutic window. These findings reveal that physiological activation of WNT/{beta}-catenin signaling via ZNRF3 and RNF43 offers a viable regenerative and metabolic strategy for reversing fatty liver disease.

cell biology↗

bioRxiv2025

In vivo anti-FAP CAR T therapy reduces fibrosis and restores liver homeostasis in metabolic dysfunction-associated steatohepatitis

In this study, we aimed to determine the efficacy of in vivo chimeric antigen receptor (CAR) T cell therapy, generated by targeted lipid nanoparticles (t-LNPs), as an anti-fibrotic in metabolic dysfunction-associated steatotic liver disease. Hepatic fibrosis is a key predictor of mortality in liver disease, driven by fibrogenic hepatic stellate cells (HSCs). In heart, chimeric antigen receptor (CAR) T cells targeting fibroblast activation protein alpha (FAP) reduce murine cardiac fibrosis. However, the value of this approach in liver is unknown. We explored the anti-fibrotic potential of in vivo-generated anti-FAP CAR T cells in metabolic dysfunction-associated steatohepatitis (MASH), a highly prevalent disease with no approved anti-fibrotic therapies. We first established that FAP expression in both human and murine MASH is specific to HSCs. We then used flow cytometry, Sirius Red morphometry, digital pathology analysis, and single nuclear RNA-sequencing to assess the impact of anti-FAP CAR T cell therapy on murine MASH. Anti-CD5 targeted-LNPs carrying anti-FAPCAR mRNA generate activated, transient anti-FAP CAR T cells, which significantly reduced fibrosis by depleting pro-fibrogenic HSCs, and by modulating immune cells, endothelial cells and hepatocytes in a non-cell autonomous manner to mitigate inflammation and restore hepatic homeostasis. These findings reinforce the potential of in vivo CAR T therapy to attenuate a highly morbid and pervasive liver disease through integrated, multicellular salutary effects. One Sentence SummaryRNA-based treatment transiently reprograms immune cells to target scar-forming cells in fatty liver disease, thus improving liver health overall.

cell biology↗