Chronic hepatitis B is caused by prolonged infection with the hepatitis B virus (HBV), which can substantially increase the risk of developing liver disease. Despite the development of preventive ...vaccines against HBV, a therapeutic vaccine inducing an effective antibody response still remains elusive. The preS1 domain of the large HBV surface protein is the major viral attachment site on hepatocytes and thus offers a therapeutic target; however, its poor immunogenicity limits clinical translation. Here, we design a ferritin nanoparticle vaccine that can deliver preS1 to specific myeloid cells, including SIGNR1
dendritic cells (which activate T follicular helper cells) and lymphatic sinus-associated SIGNR1
macrophages (which can activate B cells). This nanoparticle vaccine induces a high-level and persistent anti-preS1 response that results in efficient viral clearance and partial serological conversion in a chronic HBV mouse model, offering a promising translatable vaccination strategy for the functional cure of chronic hepatitis B.
While IL-2 can potently activate both NK and T cells, its short in vivo half-life, severe toxicity, and propensity to amplify Treg cells are major barriers that prevent IL-2 from being widely used ...for cancer therapy. In this study, we construct a recombinant IL-2 immunocytokine comprising a tumor-targeting antibody (Ab) and a super mutant IL-2 (sumIL-2) with decreased CD25 binding and increased CD122 binding. The Ab-sumIL2 significantly enhances antitumor activity through tumor targeting and specific binding to cytotoxic T lymphocytes (CTLs). We also observe that pre-existing CTLs within the tumor are sufficient and essential for sumIL-2 therapy. This next-generation IL-2 can also overcome targeted therapy-associated resistance. In addition, preoperative sumIL-2 treatment extends survival much longer than standard adjuvant therapy. Finally, Ab-sumIL2 overcomes resistance to immune checkpoint blockade through concurrent immunotherapies. Therefore, this next-generation IL-2 reduces toxicity while increasing TILs that potentiate combined cancer therapies.
Metastasis is the primary cause of cancer mortality, and cancer frequently metastasizes to the liver. It is not clear whether liver immune tolerance mechanisms contribute to cancer outcomes. We ...report that liver metastases diminish immunotherapy efficacy systemically in patients and preclinical models. Patients with liver metastases derive limited benefit from immunotherapy independent of other established biomarkers of response. In multiple mouse models, we show that liver metastases siphon activated CD8
T cells from systemic circulation. Within the liver, activated antigen-specific Fas
CD8
T cells undergo apoptosis following their interaction with FasL
CD11b
F4/80
monocyte-derived macrophages. Consequently, liver metastases create a systemic immune desert in preclinical models. Similarly, patients with liver metastases have reduced peripheral T cell numbers and diminished tumoral T cell diversity and function. In preclinical models, liver-directed radiotherapy eliminates immunosuppressive hepatic macrophages, increases hepatic T cell survival and reduces hepatic siphoning of T cells. Thus, liver metastases co-opt host peripheral tolerance mechanisms to cause acquired immunotherapy resistance through CD8
T cell deletion, and the combination of liver-directed radiotherapy and immunotherapy could promote systemic antitumor immunity.
The flow channel structure is a key core component in the fuel cell, which affects the performance of the fuel cell by affecting the distribution of the reaction gas and liquid water. To solve the ...problem of liquid water accumulation in the contact area between the flow channel and the ridge in the single flow channel of the fuel cell, a three-dimensional oblique prism flow channel was designed, and its three-dimensional structure and quantity layout was optimized, inspired by the principle of field cooperation and waveform flow field structure. Through these optimization measures, the goal of accelerating the flow of directional guiding gas to the side wall of the flow channel is successfully achieved, and the hydrophobicity of the flow channel wall is also improved. Compared with the straight channel, the liquid water saturation of the OPB-IV flow channel with
N
= 9 in the flow channel and the gas diffusion layer (GDL) was reduced by 62.7%, and the oxygen molar concentration at the interface between the GDL and the catalytic layer was increased by 19.1%. In addition, we analyzed the influence of inlet humidity on the performance of fuel cells. These optimization measures are essential for improving the performance of fuel cells, reducing costs, and promoting the development of green energy.
Strong tolerance to hepatitis B virus (HBV) surface antigens limits the therapeutic effect of the conventional hepatitis B surface antigen (HBsAg) vaccination in both preclinical animal models and ...patients with chronic hepatitis B (CHB) infection. In contrast, we observed that clinical CHB patients presented less immune tolerance to the preS1 domain of HBV large surface antigen. To study whether targeting the weak tolerance of the preS1 region could improve therapy gain, we explored vaccination with the long peptide of preS1 domain for HBV virions clearance. Our study showed that this preS1‐polypeptide rather than HBsAg vaccination induced robust immune responses in HBV carrier mice. The anti‐preS1 rapidly cleared HBV virions in vivo and blocked HBV infection to hepatocytes in vitro. Intriguingly, vaccination of preS1‐polypeptide even reduced the tolerized status of HBsAg, opening a therapeutic window for the host to respond to the HBsAg vaccine. A sequential administration of antigenically distinct preS1‐polypeptide and HBsAg vaccines in HBV carrier mice could finally induce HBsAg/hepatitis B surface antibody serological conversion and clear chronic HBV infection in carrier mice. Conclusion: These results suggest that preS1 can function as a therapeutic vaccine for the control of CHB. (Hepatology 2017;66:1067‐1082)
Key message
We fine-mapped
QBp.caas-3BL
for black point resistance in an interval of 1.7 Mb containing five high-confidence annotated genes and developed a KASP marker suitable for selection of
...QBp.caas-3BL
.
Wheat black point, which occurs in most wheat-growing regions of the world, is detrimental to grain appearance, processing and nutrient quality. Mining and characterization of genetic loci for black point resistance are helpful for breeding resistant wheat cultivars. We previously identified a major QTL
QBp.caas-3BL
in a recombinant inbred line (RIL) population of Linmai 2/Zhong 892 across five environments. Here we confirmed the QTL in two additional environments. The genetic region of
QBp.caas-3BL
was enriched with newly developed markers. Using four sets of near isogenic lines,
QBp.caas-3BL
was narrowed down to a physical interval of approximately 1.7 Mb, including five annotated genes according to IWGSC reference genome.
TraesCS3B02G404300
,
TraesCS3B02G404600
and
TraesCS3B02G404700
were predicted as candidate genes based on the analyses of sequence polymorphisms and differential expression. We also converted a SNP of
TraesCS3B02G404700
into a breeding-applicable KASP marker and verified its efficacy for marker-assisted breeding in a panel of germplasm. The findings not only lay a foundation for map-based cloning of
QBp.caas-3BL
but also provide a useful marker for selection of resistant cultivars genotypes in wheat breeding.
Tumor-associated macrophages (TAMs) affect cancer progression and therapy. Ovarian carcinoma often metastasizes to the peritoneal cavity. Here, we found 2 peritoneal macrophage subsets in mice ...bearing ID8 ovarian cancer based on T cell immunoglobulin and mucin domain containing 4 (Tim-4) expression. Tim-4+ TAMs were embryonically originated and locally sustained while Tim-4- TAMs were replenished from circulating monocytes. Tim-4+ TAMs, but not Tim-4- TAMs, promoted tumor growth in vivo. Relative to Tim-4- TAMs, Tim-4+ TAMs manifested high oxidative phosphorylation and adapted mitophagy to alleviate oxidative stress. High levels of arginase-1 in Tim-4+ TAMs contributed to potent mitophagy activities via weakened mTORC1 activation due to low arginine resultant from arginase-1-mediated metabolism. Furthermore, genetic deficiency of autophagy element FAK family-interacting protein of 200 kDa resulted in Tim-4+ TAM loss via ROS-mediated apoptosis and elevated T cell immunity and ID8 tumor inhibition in vivo. Moreover, human ovarian cancer-associated macrophages positive for complement receptor of the immunoglobulin superfamily (CRIg) were transcriptionally, metabolically, and functionally similar to murine Tim-4+ TAMs. Thus, targeting CRIg+ (Tim-4+) TAMs may potentially treat patients with ovarian cancer with peritoneal metastasis.
Grain weight and grain number are important yield component traits in wheat and identification of underlying genetic loci is helpful for improving yield. Here, we identified eight stable quantitative ...trait loci (QTL) for yield component traits, including five loci for thousand grain weight (TGW) and three for grain number per spike (GNS) in a recombinant inbred line population derived from cross Yangxiaomai/Zhongyou 9507 across four environments. Since grain size is a major determinant of grain weight, we also mapped QTL for grain length (GL) and grain width (GW). QTGW.caas-2D, QTGW.caas-3B, QTGW.caas-5A and QTGW.caas-7A.2 for TGW co-located with those for grain size. QTGW.caas-2D also had a consistent genetic position with QGNS.caas-2D, suggesting that the pleiotropic locus is a modulator of trade-off effect between TGW and GNS. Sequencing and linkage mapping showed that TaGL3-5A and WAPO-A1 were candidate genes of QTGW.caas-5A and QTGW.caas-7A.2, respectively. We developed Kompetitive allele specific PCR (KASP) markers linked with the stable QTL for yield component traits and validated their genetic effects in a diverse panel of wheat cultivars from the Huang-Huai River Valley region. KASP-based genotyping analysis further revealed that the superior alleles of all stable QTL for TGW but not GNS were subject to positive selection, indicating that yield improvement in the region largely depends on increased TGW. Comparative analyses with previous studies showed that most of the QTL could be detected in different genetic backgrounds, and QTGW.caas-7A.1 is likely a new QTL. These findings provide not only valuable genetic information for yield improvement but also useful tools for marker-assisted selection.
Tumor cell intrinsic ferroptosis-initiating mechanisms are unknown. Here, we discover that T cell-derived interferon (IFN)γ in combination with arachidonic acid (AA) induces immunogenic tumor ...ferroptosis, serving as a mode of action for CD8+ T cell (CTL)-mediated tumor killing. Mechanistically, IFNγ stimulates ACSL4 and alters tumor cell lipid pattern, thereby increasing incorporations of AA into C16 and C18 acyl chain-containing phospholipids. Palmitoleic acid and oleic acid, two common C16 and C18 fatty acids in blood, promote ACSL4-dependent tumor ferroptosis induced by IFNγ plus AA. Moreover, tumor ACSL4 deficiency accelerates tumor progression. Low-dose AA enhances tumor ferroptosis and elevates spontaneous and immune checkpoint blockade (ICB)-induced anti-tumor immunity. Clinically, tumor ACSL4 correlates with T cell signatures and improved survival in ICB-treated cancer patients. Thus, IFNγ signaling paired with selective fatty acids is a natural tumor ferroptosis-promoting mechanism and a mode of action of CTLs. Targeting the ACSL4 pathway is a potential anti-cancer approach.
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•Arachidonic acid and IFNγ coordinately induce tumor cell ferroptosis via ACSL4•ACSL4-dependent tumor ferroptosis is a mode of action of CTLs•ACSL4 mediates immunogenic tumor ferroptosis•Targeting tumor ACSL4 sensitizes checkpoint therapy
In brief: Liao et al. demonstrate IFNγ from cytotoxic T lymphocytes (CTLs) and arachidonic acid from the tumor microenvironment naturally induce tumor cell ferroptosis, which is mediated via ACSL4-dependent lipid reprogramming. Targeting the ACSL4 pathway is a potential anti-cancer approach.
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