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GDF15 (growth differentiation factor 15), also known as macrophage inhibitory cytokine 1 (MIC-1), is a circulating protein involved in the regulation of energy balance and weight control. Elevated levels of GDF15 have been associated with cachexia and reduced survival rates in cancer patients. Through the activation of the GFRAL (GDNF-family receptor α-like)-RET (Rearranged during Transfection) signaling pathway, GDF15 can induce weight loss, making it a potential target for treating cachexia. Currently, there are no approved antibody drugs specifically targeting GDF15 for cancer cachexia treatment. However, efforts have been made to develop antibody-based therapeutics against this emerging target. In this study, we generated a monoclonal antibody KY-NAb-GDF15 against GDF15 that effectively blocks downstream signaling mediated by GFRAL upon stimulation by GDF15. This antibody demonstrates robust neutralizing activity and exhibits high binding specificity. Importantly, our findings indicate that this antibody holds promise in alleviating cancer-induced cachexia and mitigating chemotherapy-induced weight loss, thereby offering significant therapeutic potential for managing cancer cachexia.

Hippo signaling restricts tissue growth by inhibiting the transcriptional effector YAP. Here we uncover a role of Hippo signaling and a tumor suppressor function of YAP in estrogen receptor positive (ER + ) breast cancer. We find that inhibition of Hippo/MST1/2 or activation of YAP blocks the ERα transcriptional program and ER + breast cancer growth. Mechanistically, the Hippo pathway transcription factor TEAD physically interacts with ERα to increase its promoter/enhancer occupancy whereas YAP inhibits ERα/TEAD interaction, decreases ERα occupancy on its target promoters/enhancers, and promotes ERα degradation by the proteasome. Furthermore, YAP inhibits hormone-independent transcription of ERα gene ( ESR1 ). Consistently, high levels of YAP correlate with good prognosis of ER + breast cancer patients. Finally, we find that pharmacological inhibition of Hippo/MST1/2 impeded tumor growth driven by hormone therapy resistant ERα mutants, suggesting that targeting the Hippo-YAP-TEAD signaling axis could be a potential therapeutical strategy to overcome endocrine therapy resistance conferred by ERα mutants. Recent studies have reported that oncoprotein YAP can function as tumour suppressor in certain contexts. Here the authors show that inhibition of Hippo signalling or YAP activation blocks ERα transcriptional program and ER + breast cancer growth and mechanistically this is through YAP interfering with TEAD-ERα signalling axis.

In leukemic mice, fasting reduces the development of acute lymphoblastic leukemia, but not acute myeloid leukemia, via upregulation of leptin receptor expression and signaling in the leukemic cells. New therapeutic approaches are needed to treat leukemia effectively. Dietary restriction regimens, including fasting, have been considered for the prevention and treatment of certain solid tumor types. However, whether and how dietary restriction affects hematopoietic malignancies is unknown. Here we report that fasting alone robustly inhibits the initiation and reverses the leukemic progression of both B cell and T cell acute lymphoblastic leukemia (B-ALL and T-ALL, respectively), but not acute myeloid leukemia (AML), in mouse models of these tumors. Mechanistically, we found that attenuated leptin-receptor (LEPR) expression is essential for the development and maintenance of ALL, and that fasting inhibits ALL development by upregulation of LEPR and its downstream signaling through the protein PR/SET domain 1 (PRDM1). The expression of LEPR signaling-related genes correlated with the prognosis of pediatric patients with pre-B-ALL, and fasting effectively inhibited B-ALL growth in a human xenograft model. Our results indicate that the effects of fasting on tumor growth are cancer-type dependent, and they suggest new avenues for the development of treatment strategies for leukemia.

The role of glycan-binding proteins as an activator of immune regulatory receptors has gained attention recently. We report that galectin 7 reduced CD4+ T cell percentage in both in vitro culture and mouse tumor models. Immunohistochemical staining of esophageal cancer patient samples showed a lower percentage of CD4+ cells in the galectin 7 high area. The lack of CD4+ T cell depletion by galectin 7 in PD-1 knockout mice supports the role of PD-1 in mediating the effects of galectin 7. The binding assays demonstrate that galectin 7 binds to the N -glycosylation of PD-1 on N74 and N116 sites and leads to the recruitment of SHP-2. NFAT suppressive activity of galectin 7 was abrogated upon overexpression of the dominant negative SHP-2 mutant or inhibition of PD-1 by siRNA. Glycosylation of PD-1 has been reported to play a critical role in surface expression, stability, and interaction with its ligand PD-L1. This report further expands the significance of PD-1 glycosylation and suggests that galectin 7, a glycan-binding protein, interacts with the immune regulatory receptor PD-1 through glycosylation recognition.

Background The utilization of liver grafts from hepatitis B core antibody (HBcAb)-positive donors is relatively common in regions with high hepatitis B virus (HBV) prevalence. This practice poses a potential risk of HBV transmission. However, the impact of these grafts on pediatric liver transplant recipients is not well-established. Method To address these knowledge gaps, we conducted a prospective observational cohort study to assess the risk of post-transplant HBV transmission in pediatric recipients of HBcAb-positive grafts. Hepatitis B serology and liver tissue analyses for HBV DNA were performed during post-transplantation follow-up of 188 pediatric recipients. Results In the cohort study, 43 pediatric recipients (22.9%) received HBcAb-positive grafts, while 145 (77.1%) received HBcAb-negative grafts. Over a median follow-up of 43 weeks, 10 recipients (5.3% of the total cohort) developed HBV infection. The cumulative incidence of de novo HBV infection was significantly higher in recipients of HBcAb-positive grafts (18%, 95% CI: 5–31) compared to recipients of HBcAb-negative grafts (3%, 95% CI: 0–6, p  < 0.05). Notably, higher levels of hepatitis B surface antibody (HBsAb ≥ 100mIU/ml) in pediatric recipients were associated with a significantly reduced risk of post-transplant de novo HBV infection ( p  < 0.05). Conclusion HBcAb-positive grafts substantially increase HBV transmission risk in pediatric liver transplantation. Elevated HBsAb titers may mitigate infection severity, while occult HBV infections require vigilant monitoring. Strategic enhancement of recipient HBsAb levels and optimized prophylactic protocols are critical for improving outcomes.

Background Estrogen receptor alpha (ER alpha) is expressed in the majority of breast cancers and promotes estrogen-dependent cancer progression. ER alpha positive breast cancer can be well controlled by ER alpha modulators, such as tamoxifen. However, tamoxifen resistance is commonly observed by altered ER alpha signaling. Thus, further understanding of the molecular mechanisms, which regulates ER alpha signaling, is important to improve breast cancer therapy. Methods SMURF1 and ER alpha protein expression levels were measured by western blot, while the ER alpha target genes were measured by real-time PCR. WST-1 assay was used to measure cell viability; the xeno-graft tumor model were used for in vivo study. RNA sequencing was analyzed by Ingenuity Pathway Analysis. Identification of ER alpha signaling was accomplished with luciferase assays, real-time RT-PCR and Western blotting. Protein stability assay and ubiquitin assay was used to detect ER alpha protein degradation. Immuno-precipitation based assays were used to detect the interaction domain between ER alpha and SMURF1. The ubiquitin-based Immuno-precipitation based assays were used to detect the specific ubiquitination manner happened on ER alpha. Results Here, we identify the E3 ligase SMURF1 facilitates ER alpha signaling. We show that depletion SMURF1 decreases ER alpha positive cell proliferation in vitro and in vivo. SMURF1 depletion based RNA-sequence data shows SMURF1 is necessary for ER alpha target gene expression in the transcriptomic scale. Immunoprecipitation indicates that SMURF1 associates with the N-terminal of ER alpha in the cytoplasm via its HECT domain. SMURF1 increases ER alpha stability, possibly by inhibiting K48-specific poly-ubiquitination process on ER alpha protein. Interestingly, SMURF1 expression could be induced via estradiol treatment. Conclusions Our study reveals a novel positive feedback between SMURF1 and ER alpha signaling in supporting breast cancer growth. Targeting SMURF1 could be one promising strategy for ER alpha positive breast cancer treatment.

BackgroundCurrent immune checkpoint blockade strategies have been successful in treating certain types of solid cancer. However, checkpoint blockade monotherapies have not been successful against most hematological malignancies including multiple myeloma and leukemia. There is an urgent need to identify new targets for development of cancer immunotherapy. LILRB1, an immunoreceptor tyrosine-based inhibitory motif-containing receptor, is widely expressed on human immune cells, including B cells, monocytes and macrophages, dendritic cells and subsets of natural killer (NK) cells and T cells. The ligands of LILRB1, such as major histocompatibility complex (MHC) class I molecules, activate LILRB1 and transduce a suppressive signal, which inhibits the immune responses. However, it is not clear whether LILRB1 blockade can be effectively used for cancer treatment.MethodsFirst, we measured the LILRB1 expression on NK cells from cancer patients to determine whether LILRB1 upregulated on NK cells from patients with cancer, compared with NK cells from healthy donors. Then, we developed specific antagonistic anti-LILRB1 monoclonal antibodies and studied the effects of LILRB1 blockade on the antitumor immune function of NK cells, especially in multiple myeloma models, in vitro and in vivo xenograft model using non-obese diabetic (NOD)-SCID interleukin-2Rγ-null mice.ResultsWe demonstrate that percentage of LILRB1+ NK cells is significantly higher in patients with persistent multiple myeloma after treatment than that in healthy donors. Further, the percentage of LILRB1+ NK cells is also significantly higher in patients with late-stage prostate cancer than that in healthy donors. Significantly, we showed that LILRB1 blockade by our antagonistic LILRB1 antibody increased the tumoricidal activity of NK cells against several types of cancer cells, including multiple myeloma, leukemia, lymphoma and solid tumors, in vitro and in vivo.ConclusionsOur results indicate that blocking LILRB1 signaling on immune effector cells such as NK cells may represent a novel strategy for the development of anticancer immunotherapy.

Background We recently identified the human leukocyte immunoglobulin-like receptor B2 (LILRB2) and its mouse ortholog-paired Ig-like receptor (PirB) as receptors for several angiopoietin-like proteins (Angptls). We also demonstrated that PirB is important for the development of acute myeloid leukemia (AML), but exactly how an inhibitory receptor such as PirB can support cancer development is intriguing. Results Here, we showed that the activation of Ca (2+)/calmodulin-dependent protein kinases (CAMKs) is coupled with PirB signaling in AML cells. High expression of CAMKs is associated with a poor overall survival probability in patients with AML. Knockdown of CAMKI or CAMKIV decreased human acute leukemia development in vitro and in vivo. Mouse AML cells that are defective in PirB signaling had decreased activation of CAMKs, and the forced expression of CAMK partially rescued the PirB-defective phenotype in the MLL-AF9 AML mouse model. The inhibition of CAMK kinase activity or deletion of CAMKIV significantly slowed AML development and decreased the AML stem cell activity. We also found that CAMKIV acts through the phosphorylation of one of its well-known target (CREB) in AML cells. Conclusion CAMKs are essential for the growth of human and mouse AML. The inhibition of CAMK signaling may become an effective strategy for treating leukemia.

Background and aims: The transplacental vertical transfer of maternal antibodies was determined to be a crucial factor in conferring protective immunity to infants following delivery, and this study aimed to evaluate the protective effect of maternal preconception COVID-19 vaccination on infants. Methods: A prospective cohort study was conducted at the National Clinical Medical Research Center for Child Health and Diseases in Chongqing, China, spanning from July 2022 to April 2023. The study included infants from mothers with a preconception COVID-19 vaccination and (or) a SARS-CoV-2 infection during pregnancy. Titers of SARS-CoV-2 immunoglobulin G (IgG) and cross-neutralizing activity against SARS-CoV-2 variants were detected. Results: In this cohort study comprising 158 infants, it was observed that infants born to mothers who experienced a pregnancy-related breakthrough infection following a preconception vaccination had the highest titers of SARS-CoV-2 IgG and cross-neutralizing antibody activity against different variants compared to those with either of these factors alone. The transplacental vertical transmission of anti-SARS-CoV-2 antibodies decreased significantly with increasing age, from 3.16 ODs at birth to 2.29 ODs at two months, and persisted for approximately four months after birth. The predominant subclass of passively transmitted antibodies via the placenta was found to be IgG1, and a positive correlation was observed between the titers of SARS-CoV-2 IgG and IgG1 (R = 0.59, p < 0.001; Slope: 0.49 ± 0.070, p < 0.001). Conclusions: Maternal preconception COVID-19 vaccination represents a promising immunological strategy for conferring postnatal protection to infants, especially during the period of heightened risk of exposure to SARS-CoV-2 infection. It is imperative to underscore the significance of vaccination for women who are preparing to become pregnant or are pregnant, and concerted efforts must be made to promote vaccination among eligible women.

BackgroundTumor necrosis factor receptor-2 (TNFR2), representing co-stimulatory and survival signaling, is selectively expressed on immune cells, especially Treg and memory T cells, promoting both Tregs and cytotoxic T cells proliferation. Due to the paradoxical functions, two types of TNFR2 antibodies are under development: depletion or agonistic antibody. The depletion antibodies eliminate TNFR2+ Tregs and MDSC through ADCC or CDC, while the agonistic antibodies activate and expand cytotoxic T cells to inhibit tumors. Here, we report a novel TNFR2 agonistic antibody, LBL-019, which preferentially activates CD8+ T cells compared to CD4+ T cells, and in addition, can alleviate the suppressive effect of Treg cells.MethodsA diverse panel of antibodies against TNFR2 was screened and developed using mouse hybridoma technology. Robust in vitro assessments of candidates, including TNFR2 binding, TNF-α blockade, NF-κB report gene and cell functional assays validated and identified LBL-019 as the lead therapeutic candidate. In vivo, efficacy of LBL-019 and its combination with PD-1 antibody was evaluated in MC38 tumor models.ResultsLBL-019 is a human/cyno cross-reactive TNFR2 antibody that binds TNFR2 with high affinity and specificity and recognizes a unique epitope in the CRD1 domain of TNFR2; LBL-019 is a potent agonist and blocks the TNFR2-TNF-α interaction in cell-based ligand binding assays and activating downstream NF-κB signal independent of TNF-α. LBL-019 plays anti-tumor efficacy through two distinct mechanisms. Firstly, it preferentially stimulated a 200% expansion of CD8 T cells compared to a 30% increase in CD4+ T cells, triggered the release of IFN-γ and up-regulated the expression of activation maker such as CD25, PD-1, and 41BB, depending on Fc crosslinking. Secondly, LBL-019 could alleviate the inhibitory effects of Treg cells on CD4/CD8 T cells, thereby promoting T cell proliferation and activation. Moreover, the combinational efficacy of LBL-019 with anti-PD1 has been demonstrated in vitro and in vivo, inhibiting tumor growth in the MC38 tumor model (TGI=80%).ConclusionsLBL-019 is a potent TNFR2 agonistic antibody. It effectively activated TNFR2 downstream signaling independent of TNF-α. By preferentially co-stimulating CD8+ T cells, LBL-019 promoted cytotoxic T cells proliferation and activation, and counteracted the immunosuppressive function of Tregs cells. The in-vitro and in-vivo anti-tumor activity of LBL-019 was evaluated both as a monotherapy and in combination with an anti-PD-1 antibody. The results demonstrate potent anti-tumor efficacy, supporting the advancement of LBL-019 in clinical development for the treatment of various human tumors.