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.
Introduction: Inactivated parapoxvirus ovis (iPPVO) exerts strong immunomodulatory effects on innate immune cells, making it an attractive therapeutic candidate. However, little is known about the ...signaling pathways involvIing in iPPVO-induced immune responses. Methods: In this study, we systematically analyzed how different types of dendritic cells (DCs) react to iPPVO (Zylexis, strain D1710) in both BALB/c and C57BL/c mice by Flow cytometry and ELISAs, and investigated which signaling pathway is related to DC activation by Western blotting and Protein profiling. Results: We demonstrated that bone marrow-derived conventional DCs (BM-cDCs) and bone marrow-derived plasmacytoid DCs (BM-pDCs) matured and secreted IFN-α/β in response to Zylexis stimulation in both mouse strains. Similarly, Zylexis promoted the secretion of IL-12/23p40 and TNF by pDCs. However, IL-12/23p40 and TNF secretion by cDCs was induced in BALB/c mice but not in C57BL/6 mice. Analyzing the underlying signaling pathways revealed that iPPVO-induced maturation of cDCs was TLR9 independent, while the maturation of pDCs partially depended on the TLR9 pathway. Moreover, the production of proinflammatory cytokines by cDCs and the secretion IFN-α/β by pDCs partially depended on the TLR9 pathway in both mouse strains. Therefore, other signaling pathways seem to participate in the response of DCs to iPPVO, supported by protein profiling.Conclusion: Our data provide useful insights into the diversity of iPPVO sensors and their varying effects across different strains and species.
Schistosomiasis is a neglected tropical disease (NTD) caused by blood-dwelling flatworms which develop from skin-penetrating cercariae, the freely swimming water-borne infective stage of
, into adult ...worms. This natural course of infection can be mimicked in experimental mouse models of schistosomiasis. However, only a maximum of 20-30% of penetrated cercariae mature into fecund adults. The reasons for this are unknown but could potentially involve soluble factors of the innate immune system, such as complement factors and preexisting, natural antibodies.
Using our recently developed novel serum- and cell-free
culture system for newly transformed schistosomula (NTS), which supports long-term larval survival, we investigated the effects of mouse serum and its major soluble complement factors C1q, C3, C4 as well as preexisting, natural IgM
and assessed worm development
by infecting complement and soluble (s)IgM-deficient animals.
In contrast to sera from humans and a broad variety of mammalian species, serum from mice, surprisingly, killed parasites already at skin stage
. Interestingly, the most efficient killing component(s) were heat-labile but did not include important members of the perhaps best known family of heat-labile serum factors, the complement system, nor consisted of complement-activating natural immunoglobulins. Infection of complement C1q and sIgM-deficient mice with
as well as
tests with sera from mice deficient in C3 and C4 revealed no major role for these soluble factors
in regard to parasite maturation, fecundity and associated immunopathology. Rather, the reduction of parasite maturation from cercariae to adult worms was comparable to wild-type mice.
This study reveals that not yet identified heat-labile serum factors are major selective determinants of the host-specificity of schistosomiasis, by directly controlling schistosomal development and survival.
Helicobacter pylori chronically colonizes the stomach and is strongly associated with gastric cancer. Its concomitant occurrence with helminths such as schistosomes has been linked to reduced cancer ...incidence, presumably due to suppression of H. pylori-associated pro-inflammatory responses. However, experimental evidence in support of such a causal link or the mutual interaction of both pathogens is lacking. We investigated the effects of co-infection during the different immune phases of S. mansoni infection. Surprisingly, co-infected mice had increased H. pylori gastric colonization during the interferon gamma (IFNγ) phase of schistosome infection but reduced infiltration of T cells in the stomach due to misdirection of antigen-experienced CXCR3+ T cells to the liver. Unexpectedly, H. pylori co-infection resulted in partial protection from schistosome-induced liver damage. Here, we demonstrate that an increase in fibrosis-protective IL-13Ra2 is associated with H. pylori infection. Thus, our study strongly points to an immunological interaction of anatomically isolated pathogens, eventually resulting in altered disease pathology.
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•Co-infection of H. pylori and S. mansoni results in altered disease-specific pathology•S. mansoni infection induces misdirection of H. pylori-associated CXCR3+ T cells•Immune misdirection of cells is helminth-immune-phase dependent•H. pylori infection ameliorates schistosome-associated liver fibrosis
Co-infection is ubiquitous in human populations and is yet not the most widely studied experimental topic. Bhattacharjee et al. demonstrate that the immunological interaction of two prominent, anatomically isolated human pathogens, H. pylori and S. mansoni, eventually results in an unusual, mutually ameliorating effect on the detrimental course of both infections.
Cancer-associated fibroblasts (CAFs) are one of the most abundant stromal cell type in the tumor microenvironment (TME) of intrahepatic cholangiocarcinoma (iCCA), where they are actively involved in ...cancer progression through a complex network of interactions with other stromal cells. The majority of the studies investigating CAFs in iCCA have focused their attention on CAF tumor-promoting roles, remarking their potential as therapeutic targets. However, indiscriminate targeting of CAFs in other desmoplastic tumors has ended in failure with no effects or even accelerated cancer progression and reduced survival, indicating the urgent need to better understand the nuances and functions of CAFs to avoid deleterious effects. Indeed, recent single cell RNA sequencing studies have shown that heterogeneous CAF subpopulations coexist in the same tumor, some promoting- and other restricting- tumor growth. Moreover, recent studies have shown that in iCCA, diverse CAF subtypes interact differently with the cells of the TME, suggesting that CAFs may dynamically change their phenotypes during tumor progression, a field that remains uninvestigated. The characterization of heterogenous CAF subpopulations and their functionality, will provide a feasible and safer approach to facilitate the development of new therapeutic approaches aimed at targeting CAFs and their interactions with other stromal cells in the TME rather than solely tumor cells in iCCA. Here, we discuss the origin of CAFs, as well as their heterogeneity, plasticity, mechanisms and targeting strategies to provide a brief snapshot of the current knowledge in iCCA.
Cancer-associated fibroblasts (CAF) are a poorly characterized cell population in the context of liver cancer. Our study investigates CAF functions in intrahepatic cholangiocarcinoma (ICC), a highly ...desmoplastic liver tumor. Genetic tracing, single-cell RNA sequencing, and ligand-receptor analyses uncovered hepatic stellate cells (HSC) as the main source of CAF and HSC-derived CAF as the dominant population interacting with tumor cells. In mice, CAF promotes ICC progression, as revealed by HSC-selective CAF depletion. In patients, a high panCAF signature is associated with decreased survival and increased recurrence. Single-cell RNA sequencing segregates CAF into inflammatory and growth factor-enriched (iCAF) and myofibroblastic (myCAF) subpopulations, displaying distinct ligand-receptor interactions. myCAF-expressed hyaluronan synthase 2, but not type I collagen, promotes ICC. iCAF-expressed hepatocyte growth factor enhances ICC growth via tumor-expressed MET, thus directly linking CAF to tumor cells. In summary, our data demonstrate promotion of desmoplastic ICC growth by therapeutically targetable CAF subtype-specific mediators, but not by type I collagen.
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•The majority of CAF in ICC are derived from hepatic stellate cells•Inflammatory CAF promote ICC through HGF and its receptor MET•myCAF promote ICC through Has2/hyaluronic acid•CAF-derived type I collagen contributes to stiffness but does not promote ICC growth
Intrahepatic cholangiocarcinoma (ICC) is an extraordinarily stiff liver tumor due to abundant scar-forming cancer-associated fibroblasts (CAF). Here, Affo et al. determine the origin and functions of CAF, and uncover distinct CAF subsets, promoting ICC growth via different therapeutically targetable mediators. Thus, CAF and their mediators may serve as therapeutic targets for ICC.
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.
Prenatal exposure to infections can modify immune development. These environmental disturbances during early life potentially alter the incidence of inflammatory disorders as well as priming of ...immune responses. Infection with the helminth Schistosoma mansoni is widely studied for its ability to alter immune responsiveness and is associated with variations in coinfection, allergy, and vaccine efficacy in endemic populations.
Exposure to maternal schistosomiasis during early life, even without transmission of infection, can result in priming effects on offspring immune responses to bystander antigenic challenges as related to allergic responsiveness and vaccination, with this article seeking to further clarify the effects and underlying immunologic imprinting.
Here, we have combined a model of chronic maternal schistosomiasis infection with a thorough analysis of subsequent offspring immune responses to allergy and vaccination models, including viral challenge and steady-state changes to immune cell compartments.
We have demonstrated that maternal schistosomiasis alters CD4+ responses during allergic sensitization and challenge in a skewed IL-4/B-cell–dominant response to antigenic challenge associated with limited inflammatory response. Beyond that, we have uncovered previously unidentified alterations to CD8+ T-cell responses during immunization that are dependent on vaccine formulation and have functional impact on the efficacy of vaccination against viral infection in a murine hepatitis B virus model.
In addition to steady-state modifications to CD4+ T-cell polarization and B-cell priming, we have traced these modified CD8+ responses to an altered dendritic cell phenotype sustained into adulthood, providing evidence for complex priming effects imparted by infection via fetomaternal cross talk.
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