CD40 expression

Collectively, CD40 expression in poorly differentiated HCC cells prevents cell death by interacting with CD40L in activated T cells. Targeting CD40 may represent a promising anticancer therapy.

Our study data demonstrate that IE1 or IE1mut vaccination has a favorable effect in glioma mice models. This study holds substantial implications for identifying new and effective therapeutic targets within GBM.

Specific activation of CD40-mediated signaling of immune cells was demonstrated with the two highest receptor-expressing cell lines, Level 2/3 and Level 4, while low-to-none in the low-expressing cell lines. The concept of receptor tuning and the presented co-culture protocol may be of general utility for assessing and developing novel bi-specific antibodies for immuno-oncology applications.

Moreover, decreased expression of CD40 in EMRECs enhanced TGF-β-induced EndoMT, suggesting that CD40 expressed during partial EndoMT inhibits transition to full EndoMT. The present findings provide a better understanding of the mechanisms underlying TGF-β-induced EndoMT and will facilitate the development of novel therapeutic strategies targeting EndoMT-driven cancer progression and metastasis.

XFab-α4-1BB/CD40L is capable of enhancing antitumour immunity by modulating dendritic cell and T-cell functions via targeting 4-1BB agonism to areas of CD40 expression. The focused, potent, and safe immune response induced by the bispecific antibody supports further clinical investigations for the treatment of solid tumours.

The -1T > C SNP of the CD40 gene is a risk factor for T2D. Depending on the genotype, it differentially affects gene expression in human cultured EC. CC-genotype HUVEC adopt a pro-inflammatory and intermediate EndMT-like phenotype in a pro-diabetic microenvironment.

In summary, IRF4 expression in GC and lymphoma B cells regulates immune signaling with PU.1 and E2A, thereby modulating antigen-dependent immune responses with potential implications for lymphomagenesis. Future studies investigating targeting of IRF4 in lymphoma are warranted.

O + D demonstrated no new toxicity concerns and yielded a clinically meaningful PFS6 rate and durable OTRs across several cancers with HRR defects, including rare cancers.

Sotigalimab plus nivolumab had a favorable safety profile consistent with the toxicity profiles of each agent. The combination resulted in durable and prolonged responses in a subset of patients with anti-PD-1-resistant melanoma, warranting further evaluation in this setting.

In line with this, ETC plus mTOR inhibition synergistically counteracted VEN resistance. These findings link oxidative CLL metabolism to CD40 expression and cellular signaling, and may hold clinical potential.

We found that the proportion of CD40 distribution in tumor cells and immune cells may be associated with this heterogeneity. The expression of CD40 in different endometrial cancers may indicate the difference prognosis, which may become a potential target for drug treatment of non-endometrioid endometrial carcinoma.

Collectively, these results suggest the possibility to activate CD40 in a PDGFRB-targeted manner in vitro. This encourages further investigation and the development of such an approach for the treatment of solid cancers.

By providing insights into the widely divergent immunologic profiles of LNENs, our results might serve as a basis for the development of novel immunotherapy-related approaches in these devastating malignancies.

Together, these findings identify a novel effect of ibrutinib: interruption of TLR9-induced CD40 upregulation and translation of pro-survival proteins. This mechanism may potentially further inhibit priming of CLL cells in the LN microenvironment for venetoclax resistance.

Moreover, the GMPA signature scores were significantly negatively correlated with EMMPRIN (CD147) and positively correlated with CD40LG expression at the transcriptomic level in most cancer patient samples from the TCGA cohort and on-treatment samples from anti-PD1 therapy cohorts. The results of this study provide an important theoretical basis for the use of GMPA signatures, as well as GPVI-EMMPRIN and GPVI-CD40LG pathways, to predict the responses of cancer patients to various types of ICB therapy.

Taken together, this study supports the role of immune checkpoint molecules and implicates the TNFR superfamily as key players in immunotherapy response in our cohort of HNSCC. Validation of these findings in a prospective study is required to determine the robustness of these tissue signatures.

Together, these findings identify a novel effect of ibrutinib: interruption of TLR9-induced CD40 upregulation and translation of pro-survival proteins. This mechanism further inhibits priming of CLL cells in the LN microenvironment for venetoclax resistance. Chronic lymphocytic leukemia, CD40, ibrutinib, Venetoclax

Jak1 inhibitor, CYT387 (2-16 micromolar), and ERK1/2 inhibitor, U0126 (5-80 micromolar), reduced CD40 expression in HLF cells under IFN-gamma stimulation. CD40 expression in poorly differentiated HCC cells is possibly regulated by CD4+T cells and IFN-gamma. A high level of soluble CD40 in the plasma of HCV-SVR patients may indicate the risk of HCC development.

[4] Sanz, I. et al. Front Immunol 10, 2458 (2019).

In vivo studies using human CD40 transgenic mice bearing CEA-transfected MC38 tumors showed superior anti-tumor effects of ATOR-4066 compared to a CD40 mAb, demonstrating the ability of ATOR-4066 to efficiently induce a tumor-targeting immune response. Overall, these data show the ability of ATOR-4066 to remodel the immune microenvironment and activate tumor-infiltrating immune cells in primary human tumors expressing CEA, demonstrating the promise of this new candidate drug for further clinical development.

The high percentage of tumor cells expressing CD40 in each of these solid tumors should be considered in the development of therapeutic agents designed to target CD40.

To be specific, 6-Keto-PGE1, 8,9-DHET, 11 (R)-HETE, 12-Keto-LTB4, 12-OxoETE, 15 (S)-HETE, 15-Deoxy-Delta12,14-PGJ2, 15-Keto-PGF2a, 20-COOH-LTB4, Lecithin, PGA2, PGB2, PGE2, PGF2a, PGG2, Prostacyclin were significantly upregulated in the leonurine group than in the control group, while Arachidonic Acid and TXB2 were significantly downregulated in the leonurine group than in the control group. Leonurine significantly promotes the maturation of moDCs derived from HDs and MM patients, the mechanism of which is related to arachidonic acid metabolism.

D2C7-IT+αCD40 treatment stimulated intratumoral CD8 T cell proliferation and generated cures in glioma-bearing mice despite FTY720-induced peripheral T cell sequestration. To determine potential translation, immunohistochemistry staining confirmed CD40 expression in human GBM tissue sections. These promising preclinical data allowed us to initiate a phase 1 study with D2C7-IT+αhCD40 in patients with malignant glioma (NCT04547777) to further evaluate this treatment in humans.

Li, J., Byrne, K. T., Yan, F., Yamazoe, T., Chen, Z., Baslan, T., Richman, L. P., Lin, J. H., Sun, Y. H., Rech, A. J., Balli, D., Hay, C. A., Sela, Y., Merrell, A. J., Liudahl, S. M., Gordon, N., Norgard, R. J., Yuan, S., Yu, S., Chao, T., Ye, S., Eisinger-Mathason, T. S. K., Faryabi, R. B., Tobias, J. W., Lowe, S. W., Coussens, L. M., Wherry, E. J., Vonderheide, R. H. & Stanger, B. Z. Tumor Cell-Intrinsic Factors Underlie Heterogeneity of Immune Cell Infiltration and Response to Immunotherapy. Immunity 49, 178-193.e7 (2018).

As anti-CD40 is known to work mostly on immune cells in other tumor models, our findings highlight direct tumor effects of CD40 agonism in GIST including decreasing cell viability, decreasing Kit signaling, and stimulating tumor cell defense anti-inflammatory responses. Learning Objectives: Upon completion, participants will be able to list two direct anti-tumor effects of anti-CD40 on GIST tumor cells. Upon completion, participants will be able to list one direct tumor cell compensatory response to anti-CD40 treatment.

CD40 expression supports the B-cell lineage and is expressed in the overwhelming majority of CHL and is not seen in cases of ALK-negative or ALK-positive ALCLs. A proportion of BIA-ALCL can express CD40 but given the unique clinical context BIA-ALCL is unlikely to be a diagnostic challenge. Our data suggests that CD40 is a useful diagnostic tool to distinguish between challenging CD30-positive LPD cases.

In vitro, 10 µM pomalidomide enhances the maturation of moDCs derived from both HDs and MM patients. Pomalidomide shows potential to be applied as a DC adjuvant for DC-based immunotherapy, such as the DC vaccine and DC cell therapy in MM.

We also identified several putative mechanisms of immune escape used by KSHV, as KIV displayed an overall decrease of co-stimulatory molecules with a remarkable lack of CD40 expression and are IL-10 producing cells. The identification of this specific and easily accessible KSHV+ circulating population brings new elements in the understanding of KSHV-MCD but also raises new questions that need to be clarified.

In fact, passive transfer of MOG-immune serum or IgG into mice lacking CD40 on B cells but not DCs reconstituted autoimmune disease, which was associated with inundation of the spinal cord parenchyma by Ig and complement. These data demonstrate that CD40 supports distinct effector programs in B cells and DCs that converge to drive a CNS autoimmune disease and identify targets for intervention.

Inhibition of JAK/STAT/BST2 axis attenuated CD40-induced antiviral effect. In conclusion, a functional variant of CD40 modulates HBV clearance via regulation of the ANXA2/CD40/BST2 axis, which may shed new light on HBV personalized therapy.

All Patients gave written informed consent before taking part in the study. Consent N/A at this point

In fact, passive transfer of MOG-immune serum or IgG into mice lacking CD40 on B cells but not DCs reconstituted autoimmune disease, which was associated with inundation of the spinal cord parenchyma by Ig and complement. These data demonstrate that CD40 supports distinct effector programs in B cells and DCs that converge to drive a CNS autoimmune disease and identify targets for intervention.

The high expression of CD40LG in TME is positively correlated with the survival of patients with invasive breast cancer, suggesting its value as a potential new biomarker for predicting prognosis of the patients.

Our work is the first, systematic map and atlas of micro-anatomical and functional differences between SjS and Sicca providing critical insight in pathogenic players and therapeutic targets in these two different conditions.Acknowledgment

Conclusions We have identified a chimeric Fas-CD40 protein that is able to not only rescue FasL-mediated T-cell apoptosis, but also elicit superior proliferation and anti-tumour cytotoxicity in the presence of FasL. Figure Legend PBMCs expressing CAR alone or with Fas-TNFRs were cultured with immobilised FasL for five days, at which point cell count was analysed by flow cytometry.

Caracasine induced apoptosis through the intrinsic and extrinsic pathway in both cell lines evaluated and may be an important leader structure for new anti-leukemic and anti-inflammatory drugs.

Mitazalimab, administered repeatedly together with FOLFIRINOX (oxaliplatin, irinotecan, 5-fluorouracil and folinic acid), synergized effectively with chemotherapy, inducing long-term survival. By converting the MB49 tumor cell line resistant to FOLFIRINOX treatment, we could further demonstrate that the combination of mitazalimab and FOLFIRINOX induced a strong anti-tumor activity also in a chemoresistant variant of the MB49 cell line.In conclusion, mitazalimab synergizes effectively with chemotherapy, leading to induction of long-term survival in a preclinical tumor model by reducing immunosuppressive M2 macrophages and improving T cell responses intratumorally. These preclinical data, together with the clinical data of mitazalimab from the phase 1 study (NCT02829099), where mitazalimab was well tolerated up to 1200 μg/kg with a manageable safety profile, support the ongoing clinical phase 2 study OPTIMIZE-1 (NCT04888312) of mitazalimab in combination with chemotherapy in pancreatic cancer.

These data indicate that berberine interferes with pro-tumor macrophage polarization and IL-10 and TGF-β release but restores Tcell anti-tumor cytotoxicity in the tumor microenvironment.

We present data from an ongoing Phase 1 study (SGNS40-001) in a PDAC cohort evaluating the combination of SEA-CD40, GnP, and pembrolizumab (pembro). The combination of SEA-CD40 + GnP + pembro demonstrated a tolerable safety profile. Evidence of immune activation was observed, consistent with the proposed mechanism of action. Follow-up for response and survival are ongoing.

Moreover, higher IL-2 expression, known to be regulated by CD40 pathway, was also observed in tumors with CSF1R c.1085 genotype A_G than genotype A_A. Higher IL-2 expression generated by the interaction of CD40 ligand and CD40 between T cells and macrophages with CSF1R c.1085A>G variant is the potential mechanism explaining the different outcomes.