TNFRSF4 expression

We report a new rationally-designed bispecific-antibody (BsAb), HX009, simultaneously targeting PD1 and CD47 to improve both the efficacy and safety over the respective single-targeting agents by grafting the extracellular domain of SIRPα onto the parental anti-PD1-monoclonal antibody, HX008. The IV single-dose toxicology study with a 14-day observation revealed a maximum tolerated dose of 150 mg/kg, while the repeated-dose (once weekly for 4 weeks, 5 doses in total) study showed a highest non-severely toxic dose (HNSTD) of 15 mg/kg. The desired preclinical PK and safety profiles, along with its antitumor activity, support HX009's candidacy for its clinical development.

Considering the need for advanced probes for noninvasive in vivo monitoring of T cell activation dynamics, we propose, that our hOX40-Nbs have a great potential as imaging probes for noninvasive and longitudinal in vivo diagnostics. Quantification of OX40+ T cells in TME or IME will provide crucial insights into the activation state of infiltrating T cells, offering a valuable biomarker for assessing immune responses, predicting treatment efficacy, and guiding personalized immunotherapy strategies in patients with cancer or IMIDs.

Treg/B cells have been applied for the treatment of some murine models of inflammatory diseases, including allergic asthma, inflammatory bowel disease, collagen-induced arthritis, gout, psoriasis and primary biliary cholangitis. This review summarizes the current knowledge of Treg/B cells.

These genes functionally enriched in promoting lymphocytes proliferation and may contribute to the enhanced persistence of CAR T cells. In conclusion, these results indicated the critical role of B cells in prolonging CAR T cells longevity and enhancing anti-tumor activity, which paves the way for the therapeutic exploitation of EphA2-CAR T cells against GBM in the future.

As the OX40 pathway is critical for expansion, differentiation, and survival of effector and memory T cells, its targeting might be a promising therapeutic approach to provide sustained inhibition of pathogenic T cells and associated inflammation and broad disease control. Antibodies against OX40 [rocatinlimab (AMG 451/KHK4083) and telazorlimab (GBR 830)] or OX40L [amlitelimab (KY1005)] have shown promising results in early-phase clinical studies of moderate-to-severe AD, highlighting the importance of OX40 signaling as a new therapeutic target in AD.

Further validation confirmed that IAV-OX40L enhanced the immune response mainly by activating Th1-dominant immune cells, releasing interferon-γ and interleukin-2. Taken together, our findings demonstrate the novel chimeric influenza OV could provide a potential therapeutic strategy for combating HCC and improve the effectiveness of virotherapy for cancer therapy.

While cereblon-modulating agents, such as pomalidomide and lenalidomide, have been found to improve the immune profile, the efficacy of their impact in combination with other treatments is yet unknown. The prognostic significance for the number of immune markers is only seen in the PVd arm and none of these immune markers exhibit prognostic values in the Vd arm. This study demonstrates the importance of the immunomodulatory effects and the therapeutic benefit of adding pomalidomide to Vd treatment.

Conclusions Consistent with the findings of our previous retrospective study (2), the ongoing prospective analysis of T-cell activation of diagnosis bone marrows of patients with AML suggests that testing TCR-mediated T-cell activation potential at diagnosis may help refine risk stratification of the heterogenous ELN intermediate risk group. AML immune suppression seems to be reversible in a minority of cases with the use of selected ICI inhibitors.

If further proven, our observations may be important in prognostication and prediction of response in melanoma. Furthermore, they may point to new IO combinations for further research and have therapeutic implications towards 'heating' up tumors.

Immunohistochemistry confirmed variable PD-1, CTLA-4, and OX40 expression in the CD4 T cell rosettes. This study introduced a new pathological approach to study the CHL TME, and provided deeper insight into CD4 T cells in CHL.

This work highlights OX40L expressed by tumor cells as a marker associated with sensitivity to PD-1 axis blockade alone for treatment nave NSCLC patients with high PD-L1 expressing. OX40L expression seems to be independent from PD-L1 expression at tumor compartment level. These data support the therapeutic modulation of OX40/OX40L axis combined with PD-1 axis inhibition particularly in this subgroup of patients.

The analysis of infiltrated T-cell subset revealed that patients with a greater number of CD4+/OX40+ or CD8+/OX40+ T cells had a longer OS. Our findings indicated that OX40 shapes an inflamed tumor immune microenvironment and predicts response to immunochemotherapy, providing insights for the application of OX40 agonist in DLBCL patients.

We first reported that GIST cells could express OX40L, patients with high OX40L experienced longer RFS. The colocalization of OX40L with immune cells indicates that OX40L could be a promising potential target for immunotherapy in GIST.

Overall, our findings strongly suggested that the three-immune checkpoints score system might be useful in the prognosis and design of personalized treatments for PAAD patients. Finally, we identified OX40 as an independent potential biomarker for PAAD prognosis prediction.

OXP could increase the infiltration of immune cells in TIME to promote the anti-tumor activity of anti-PD-1 inhibitor. The present research provided an appropriate rationale of combination chemotherapy and immunotherapy therapy for BLCA.

This ongoing study, to our knowledge, represents the first digital spatial analysis of tumor biopsies from patients treated with elraglusib. These novel circulating biomarkers of response to GSK-3 inhibition could provide significant clinical utility and the spatial proteomics data may give us insights into the immunomodulatory mechanisms of GSK-3 inhibition.

These studies demonstrate that HER2 specific CD4 T cells can be successfully expanded from HER2-DC1 vaccinated patients. Post HER2 DC1 vaccine can generate a pool of antigen specific CD4 T cells and may offer a promising ACT for HER2 BC. Further studies are warranted to demonstrate the efficacy in the clinical setting.

In conclusion, the potential therapeutic effect of NK cells combined with Bev plus Iri against GBM cells was limited in this study. Accordingly, further research is required to improve the accessibility and strength of NK cell function in this combination treatment.

EMT-related features were enriched in BTC patients with poor survival outcomes and associated with regulatory T-cell infiltration.

 Based on current study findings, despite OX40 and OX40L upregulation in newly diagnosed OSCC patients, it is speculated that the physiological function of these molecules is altered due to immune system exhaustion.

As an independent prognostic marker of HCC, TNFRSF4 was found simultaneously to affect the immune infiltration of cells and the frequency of gene mutations.

Co-culture of CD8 T cells expressing OX40 with IL-33-stimulated ILC2 expressing OX40L promoted cell activation and proliferation of CD8 T cells, which was significantly suppressed by administration of anti-OX40L blocking antibody. Thus, the IL-33-ILC2 axis promotes CD8 T cell responses via OX40/OX40L interaction and exerts an anti-tumor effect.

On the basis of the costimulatory molecule expression in HCC, a novel risk model was constructed and had an excellent value to predict prognosis, immune microenvironment, and response to immune therapy. TNFRSF4 was identified as an underlying oncogene in HCC and deserves further exploration.

Along with the risk score evaluation, the ICI gene (TNFRSF4) was identified as a tumor suppressor gene related to inequalities in age survival and associated with immune cell infiltrations. The aging responses of melanoma patients and related gene expression need further investigation in order to identify potential therapeutic targets.

The area under the curve of the prediction model for OS based on clinicopathological features was improved from 0.62 to 0.74 by adding to CD8, OX40, CD68, CD66b, and TILs, whereas it was improved from 0.59 to 0.73 for the DFS prediction model. Our results, if confirmed, indicated that immune-related biomarkers should be taken into account or stratified in survival analysis for HCC.

Collectively, TNFRSF4, a previously unrecognized key player in EC, could serve as a potential biomarker for prognosis prediction and immunomodulation of EC.

We provide data supporting the viewpoint that a cohort of sarcoma patients, appropriately selected, are promising candidates for immunotherapies. Spatial profiling of OX40+ Tregs, in relation to TLSs, could be an additional metric to improve future patient stratification.

In a mouse model of residual leukemia post alloHSCT, administration of T cells co-expressing OX40 ADR and CD19 CAR mediated dual protection against tumor relapse and aGvHD. These results support the feasibility of a bi-functional CAR.ADR T cell product to improve outcomes post alloHSCT and reduce transplant-related mortality.

OX40 and OX40L are abnormally expressed in the peripheral blood of patients with MG and may be closely associated with disease status and treatment. The OX40/OX40L pathway may be involved in the immunopathological process of MG and may play a role mainly in the later stage of MG.

 OX40-targeting predominantly ablated activated CD4+ T-cells but did not impair specific antiviral T-cell responses in vitro. Targeting activated CD4+ T-cells with OX40.ADR T-cells protected mice from fatal aGvHD driven by xenoreactive human PBMCs. Finally, OX40.ADR-armed CD19.CAR T-cells mediated dual protection against leukemia relapse and aGvHD, thus supporting the feasibility of a bi-functional CAR-ADR T-cell product to reduce alloHSCT-related mortality.

 OX40-targeting predominantly ablated activated CD4+ T-cells but did not impair specific antiviral T-cell responses in vitro. Targeting activated CD4+ T-cells with OX40.ADR T-cells protected mice from fatal aGvHD driven by xenoreactive human PBMCs. Finally, OX40.ADR-armed CD19.CAR T-cells mediated dual protection against leukemia relapse and aGvHD, thus supporting the feasibility of a bi-functional CAR-ADR T-cell product to reduce alloHSCT-related mortality.

Two breast cancer patient-derived xenograft (PDX) models were treated with patritumab (anti-HER3 antibody), polyclonal activated autologous T cells (PATCs) or a combination of patritumab and PATCs (P-PATCs) in order to test immunological modulation by the regulation of HER3 signals... These data suggest that HER3 expression in breast cancer associated with “cold” TIME and the regulation of its signal converts “cold” TIME to “hot”. Thus, inhibition of HER3 signal might be of interesting concept for both regulation of oncologic signal and immunological modulation in HER3-expressing breast cancer. Further HER3 related immune modulation exploration in breast cancer treatment strategy needs to be clarified in the future.

RT+CpG+OX40 increased the ratio of tumor-infiltrating effector T cells to T regulatory cells and significantly increased CD4+ and CD8+ T cell activation in the tumor draining lymph node (TDLN) and spleen. RT significantly improves the local anti-tumor effect of the in situ vaccine CpG+OX40 in immunologically "cold", solid, murine tumor models where RT or CpG+OX40 alone fail to stimulate tumor regression.

The miOX40L-high FL group had a significantly worse overall survival than the miOX40L-low group (p=0.0320).The expression of multiple ICP molecules on several cells reflects activated anti-tumor immunity and the unique FL microenvironment. Further studies on gene expression or genomic abnormalities will reveal the clinical and biological significance of ICP molecules in FL.

This work demonstrated that PCSK9 suppressed M2-like TAM polarization by regulating the secretion of OX40L from hepatocellular carcinoma cells. This study suggests that PCSK9 may be a potential target for HCC treatment.

The low-risk samples were characterized by elevated immune cell infiltrations, stromal/immune scores, TNFRSF4 expression, and sensitivity to cisplatin. The nomogram accurately predicted 1-, 3-, and 5-years survival duration. These findings might offer an insight into the optimization of prognosis risk stratification and individualized therapy for osteosarcoma patients.

We further found significant correlations of CpG methylation with overall survival, signatures of immune cell infiltrates, an interferon-γ signature, and mutational load. Our study provides a framework to prospectively test specific CpG sites as biomarkers, in particular in the context of immunotherapies.

Collectively, this work highlighted the significance of OX40 and OX40L in prognosis and TME cell infiltration characterization of SCLC. Evaluating the OX40/OX40L-expression levels of individual patients with SCLC might contribute to guiding more precise therapy.

This in situ vaccine caused little harm to normal organs and provided long-term protection against the same syngeneic tumor rechallenge. Due to its effectiveness, feasibility and safety, this strategy could potentially be applied to various types of late-stage solid tumors and worthy of further clinical research.

Here, we report a simple and robust in vitro method to screen for immune activity potential of novel second-generation VIP-R antagonists using human T cells. Preliminary screen shows VIP-R antagonists augment activation of both CD4+ and CD8+ T cells. Our results indicate that ANT308 and ANT195 are more potent VIP-R antagonists with enhanced activity in vitro (human) and in vivo (mouse) than VIPhyb and ANT008, which demonstrate lower predicted binding affinities to VPAC1 and VPAC2.

In the BM of newly diagnosed CML patients, TNFRSF4 mRNA levels were significantly increased and correlated with the expression of the Treg-restricted transcription factor FOXP3. Overall, these results identify Tregs as key regulator of immune escape of LSCs and TNFRSF4 as a potential target to reduce the function of Tregs and boost anti-leukemic immunity in CML.