Cancer-associated fibroblasts (CAF) may exert tumor-promoting and tumor-suppressive functions, but the mechanisms underlying these opposing effects remain elusive. Here, we sought to understand these ...potentially opposing functions by interrogating functional relationships among CAF subtypes, their mediators, desmoplasia, and tumor growth in a wide range of tumor types metastasizing to the liver, the most common organ site for metastasis. Depletion of hepatic stellate cells (HSC), which represented the main source of CAF in mice and patients in our study, or depletion of all CAF decreased tumor growth and mortality in desmoplastic colorectal and pancreatic metastasis but not in nondesmoplastic metastatic tumors. Single-cell RNA-Seq in conjunction with CellPhoneDB ligand-receptor analysis, as well as studies in immune cell-depleted and HSC-selective knockout mice, uncovered direct CAF-tumor interactions as a tumor-promoting mechanism, mediated by myofibroblastic CAF-secreted (myCAF-secreted) hyaluronan and inflammatory CAF-secreted (iCAF-secreted) HGF. These effects were opposed by myCAF-expressed type I collagen, which suppressed tumor growth by mechanically restraining tumor spread, overriding its own stiffness-induced mechanosignals. In summary, mechanical restriction by type I collagen opposes the overall tumor-promoting effects of CAF, thus providing a mechanistic explanation for their dual functions in cancer. Therapeutic targeting of tumor-promoting CAF mediators while preserving type I collagen may convert CAF from tumor promoting to tumor restricting.
Hepatocellular carcinoma (HCC), the fourth leading cause of cancer mortality worldwide, develops almost exclusively in patients with chronic liver disease and advanced fibrosis
. Here we interrogated ...functions of hepatic stellate cells (HSCs), the main source of liver fibroblasts
, during hepatocarcinogenesis. Genetic depletion, activation or inhibition of HSCs in mouse models of HCC revealed their overall tumour-promoting role. HSCs were enriched in the preneoplastic environment, where they closely interacted with hepatocytes and modulated hepatocarcinogenesis by regulating hepatocyte proliferation and death. Analyses of mouse and human HSC subpopulations by single-cell RNA sequencing together with genetic ablation of subpopulation-enriched mediators revealed dual functions of HSCs in hepatocarcinogenesis. Hepatocyte growth factor, enriched in quiescent and cytokine-producing HSCs, protected against hepatocyte death and HCC development. By contrast, type I collagen, enriched in activated myofibroblastic HSCs, promoted proliferation and tumour development through increased stiffness and TAZ activation in pretumoural hepatocytes and through activation of discoidin domain receptor 1 in established tumours. An increased HSC imbalance between cytokine-producing HSCs and myofibroblastic HSCs during liver disease progression was associated with increased HCC risk in patients. In summary, the dynamic shift in HSC subpopulations and their mediators during chronic liver disease is associated with a switch from HCC protection to HCC promotion.
Diffuse large B-cell lymphoma (DLBCL) is curable in 60% of patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). MYC translocations, with or ...without BCL2 translocations, have been associated with inferior survival in DLBCL. We investigated whether expression of MYC protein, with or without BCL2 protein expression, could risk-stratify patients at diagnosis.
We determined the correlation between presence of MYC and BCL2 proteins by immunohistochemistry (IHC) with survival in two independent cohorts of patients with DLBCL treated with R-CHOP. We further determined if MYC protein expression correlated with high MYC mRNA and/or presence of MYC translocation.
In the training cohort (n = 167), MYC and BCL2 proteins were detected in 29% and 44% of patients, respectively. Concurrent expression (MYC positive/BCL2 positive) was present in 21% of patients. MYC protein correlated with presence of high MYC mRNA and MYC translocation (both P < .001), but the latter was less frequent (both 11%). MYC protein expression was only associated with inferior overall and progression-free survival when BCL2 protein was coexpressed (P < .001). Importantly, the poor prognostic effect of MYC positive/BCL2 positive was validated in an independent cohort of 140 patients with DLBCL and remained significant (P < .05) after adjusting for presence of high-risk features in a multivariable model that included elevated international prognostic index score, activated B-cell molecular subtype, and presence of concurrent MYC and BCL2 translocations.
Assessment of MYC and BCL2 expression by IHC represents a robust, rapid, and inexpensive approach to risk-stratify patients with DLBCL at diagnosis.
Regulatory T (Treg) cells are classically known for their critical immunosuppressive functions that support peripheral tolerance. More recent work has demonstrated that Treg cells produce pro-repair ...mediators independent of their immunosuppressive function, a process that is critical to repair and regeneration in response to numerous tissue insults. These factors act on resident parenchymal and structural cells to initiate repair in a tissue-specific context. This review examines interactions between Treg cells and tissue-resident non-immune cells-in the context of tissue repair, fibrosis, and cancer-and discusses areas for future exploration.
We recently developed a high throughput T cell receptor β chain (TCRβ) sequencing‐based approach to identifying and tracking donor‐reactive T cells. To address the role of clonal deletion in liver ...allograft tolerance, we applied this method in samples from a recent randomized study, ITN030ST, in which immunosuppression withdrawal was attempted within 2 years of liver transplantation. We identified donor‐reactive T cell clones via TCRβ sequencing following a pre‐transplant mixed lymphocyte reaction and tracked these clones in the circulation following transplantation in 3 tolerant and 5 non‐tolerant subjects. All subjects showed a downward trend and significant reductions in donor‐reactive TCRβ sequences were detected post‐transplant in 6 of 8 subjects, including 2 tolerant and 4 non‐tolerant recipients. Reductions in donor‐reactive TCRβ sequences were greater than those of all other TCRβ sequences, including 3rd party‐reactive sequences, in all 8 subjects, demonstrating an impact of the liver allograft after accounting for repertoire turnover. Although limited by patient number and heterogeneity, our results suggest that partial deletion of donor‐reactive T cell clones may be a consequence of liver transplantation and does not correlate with success or failure of early immunosuppression withdrawal. These observations underscore the organ‐ and/or protocol‐specific nature of tolerance mechanisms in humans.
Tolerant and nontolerant patients have reduced detection of CD4 and CD8 donor‐reactive T cell clones, suggesting that partial clonal deletion of donor‐reactive T cells may be common after human liver transplantation.
•Pt3Sn/C shows higher selectivity for decarboxylation of stearic acid than Pt/C.•Pt3Sn/C shows 3/2× the selectivity for decarboxylation of oleic/linoleic acid.•Labeled water experiments show steam ...reforming to provide hydrogen.•Higher Sn loadings led to better carbon recoveries for linoleic acid.
Decarboxylation of fatty acids is a path to fuel-range hydrocarbons from renewable plant and seed oils. Pt/C is an effective hydrothermal catalyst for decarboxylating saturated fatty acids without added hydrogen, but it has shown low selectivity and activity for decarboxylating unsaturated fatty acids, which are prevalent in plant oils from soy and algae. To develop better decarboxylation catalysts, we compared three different Sn containing alloys, Pt3Sn/C, PtSn/C, and PtSn3/C, to Pt/C by performing batch reactions in liquid water at 350°C for two hours with stearic (C18:0), oleic (C18:1), and linoleic (C18:2) acids. Pt/C gave yields of 0.70±0.05, 0.16±0.03, and 0.083±0.009 for the C17 alkane, but none of the direct decarboxylation products (i.e., C17 alkenes), for the oleic and linoleic acid feeds. Stearic acid was the major byproduct from the unsaturated fatty acids. In contrast, the PtSnx/C catalysts provided two to three times higher C17 alkane yields at identical conditions. Experiments in D2O showed that water molecules were a source of hydrogen for saturation of the fatty acids. These results show that PtSnx alloys give better performance than Pt alone for the hydrothermal conversion of renewable fatty acids to fuel range hydrocarbons.
Activated T cells drive a range of immune‐mediated inflammatory diseases. LAG‐3 is transiently expressed on recently activated CD4+ and CD8+ T cells. We describe the engineering and first‐in‐human ...clinical study (NCT02195349) of GSK2831781 (an afucosylated humanized IgG1 monoclonal antibody enhanced with high affinity for Fc receptors and LAG‐3 and antibody‐dependent cellular cytotoxicity capabilities), which depletes LAG‐3 expressing cells. GSK2831781 was tested in a phase I/Ib, double‐blind, placebo‐controlled clinical study, which randomized 40 healthy participants (part A) and 27 patients with psoriasis (part B) to single doses of GSK2831781 (up to 0.15 and 5 mg/kg, respectively) or placebo. Adverse events were generally balanced across groups, with no safety or tolerability concern identified. LAG‐3+ cell depletion in peripheral blood was observed at doses ≥ 0.15 mg/kg and was dose‐dependent. In biopsies of psoriasis plaques, a reduction in mean group LAG‐3+ and CD3+ T‐cell counts was observed following treatment. Downregulation of proinflammatory genes (IL‐17A, IL‐17F, IFNγ, and S100A12) and upregulation of the epithelial barrier integrity gene, CDHR1, was observed with the 5 mg/kg dose of GSK2831781. Psoriasis disease activity improved up to day 43 at all GSK2831781 doses (0.5, 1.5, and 5 mg/kg) compared with placebo. Depletion of LAG‐3‐expressing activated T cells is a novel approach, and this first clinical study shows that GSK2831781 is pharmacologically active and provides encouraging early evidence of clinical effects in psoriasis, which warrants further investigation in T‐cell‐mediated inflammatory diseases.
Production of amphiregulin (Areg) by regulatory T (Treg) cells promotes repair after acute tissue injury. Here, we examined the function of Treg cells in non-alcoholic steatohepatitis (NASH), a ...setting of chronic liver injury. Areg-producing Treg cells were enriched in the livers of mice and humans with NASH. Deletion of Areg in Treg cells, but not in myeloid cells, reduced NASH-induced liver fibrosis. Chronic liver damage induced transcriptional changes associated with Treg cell activation. Mechanistically, Treg cell-derived Areg activated pro-fibrotic transcriptional programs in hepatic stellate cells via epidermal growth factor receptor (EGFR) signaling. Deletion of Areg in Treg cells protected mice from NASH-dependent glucose intolerance, which also was dependent on EGFR signaling on hepatic stellate cells. Areg from Treg cells promoted hepatocyte gluconeogenesis through hepatocyte detection of hepatic stellate cell-derived interleukin-6. Our findings reveal a maladaptive role for Treg cell-mediated tissue repair functions in chronic liver disease and link liver damage to NASH-dependent glucose intolerance.
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•Treg cells are enriched and activated in human and mouse chronic liver disease•Treg cell-derived Areg promotes liver fibrosis and glucose intolerance•Areg from Treg cells activates hepatic stellate cells via EGFR signaling•Activated hepatic stellate cells promote hepatocyte gluconeogenesis via IL-6
Non-alcoholic fatty liver disease and its progressive form, non-alcoholic steatohepatitis (NASH), are a prevalent cause of chronic liver disease. Savage et al. demonstrate that regulatory T (Treg) cells are enriched in mouse and human NASH and find that production of the EGFR ligand amphiregulin by Treg cells promotes NASH-induced liver fibrosis and glucose intolerance through direct signaling to hepatic stellate cells.
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