Targeting CD40, a member of the tumor necrosis factor superfamily, using agonist antibodies (Abs) produces dramatic antitumor effects. Indeed, high-dose intravenous anti-CD40 Ab 'licenses' dendritic cells (DCs) that instruct activated CD8 + cytotoxic T cells to leave lymph nodes (LNs) and penetrate the mesothelioma tumor microenvironment. However, toxic side effects and the potential of an 'overwhelmed' immune response warrant an alternative approach. In this study, we show that injecting lower doses of anti-CD40 Ab directly into the tumor bed avoided toxic side effects and prolonged survival in 60% of mice, with most cured. Unexpectedly, DCs in tumors and LNs 'disappeared', CD8 + tumor-specific T-cell numbers and function were not enhanced, and T cells did not infiltrate regressing tumors. CD4 + or CD8 + depletion only marginally hindered anti-CD40 Ab efficacy implying another effector mechanism. B-cell numbers significantly increased in tumors, draining LNs and spleens during intratumoral anti-CD40 Ab treatment. CD40 targeting had no effect on splenic B-1 cells, obliterated marginal zone B cells and promoted follicular ( A number of tumors showed promising sensitivity to agonist anti-CD40 antibody (Ab) therapy. 1-4 Intravenous (i.v.) anti-CD40 Ab therapy is often used, yet it could lead to serious side effects and risks 'exhausting' the immune system. 2,5-7 Intratumoral (i.t.) administration of agonist anti-CD40 Ab is an alternative strategy that directly targets the tumor microenvironment and may avoid unwanted side effects. 2,6,8 In this study, we used a murine model of malignant mesothelioma (MM) because (1) it has already shown sensitivity to systemically administered anti-CD40 Ab; 3,4 (2) other immunotherapeutic agents have been effective when administered directly into MM tumors; 9-12 (3) there are MM patients with accessible tumors making this approach clinically applicable 9,13,14 and (4) the search for alternative therapies for MM is crucial as long-term survivors after standard therapies such as chemotherapy, surgery and/or irradiation remain rare. 15 Most studies using anti-CD40 Ab as an anticancer therapy recognize tumor-specific cytotoxic lymphocytes (CTLs) driven by CD40-licensed dendritic cells (DCs) as the main effector cell involved, 2,3,16 particularly when high doses of anti-CD40 Ab are delivered systemically. Yet, CD40 is a 50 kDa type I membrane glycoprotein member of the tumor necrosis factor superfamily that was initially identified as a surface marker on B cells. 17 In B cells, CD40/CD40L (CD154) interactions promote clonal expansion, differentiation, isotype switching and maturation, and lead to germinal center formation in spleen and lymph nodes (LNs). 17,18 Moreover, recent studies have reported a positive role for CD40-activated B cells in tumor immunity. [19][20][21][22] CD40-activated B cells have been also used to identify tumor antigens. 23 These studies are particularly promising as B cells are considered to have a minor role in several cancers (reviewed by Canevari et al. 24 ...
Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), is an increasing threat to global health. Available medicines were introduced over 40 years ago, have undesirable side effects, and give equivocal results of cure in the chronic stage of the disease. We report the development of two compounds, 6 and (S)-7, with PCR-confirmed curative activity in a mouse model of established T. cruzi infection after once daily oral dosing for 20 days at 20 mg/kg 6 and 10 mg/kg (S)-7. Compounds 6 and (S)-7 have potent in vitro activity, are noncytotoxic, show no adverse effects in vivo following repeat dosing, are prepared by a short synthetic route, and have druglike properties suitable for preclinical development.
The aim of the present study was to define the point at which mesothelioma T-cell responses fail in order to design better immunotherapies.A murine model of mesothelioma was used which was established with asbestos. Inoculation of tumour cells into syngeneic mice results in progressing tumours with similar histopathology to human mesothelioma. The tumour cells secrete a marker tumour antigen similar to secreted tumour-associated products, such as mesothelin.The
Myeloid leukemia factor 1 (MLF1) is an oncoprotein associated with hemopoietic lineage commitment and acute myeloid leukemia. Here we show that Mlf1 associated with a novel binding partner, Mlf1-associated nuclear protein (Manp), a new heterogenous nuclear ribonucleoprotein (hnRNP) family member, related to hnRNP-U. Manp localized exclusively in the nucleus and could redirect Mlf1 from the cytoplasm into the nucleus. The nuclear content of Mlf1 was also regulated by 14-3-3 binding to a canonical 14-3-3 binding motif within the N terminus of Mlf1. Significantly Mlf1 contains a functional nuclear export signal and localized primarily to the nuclei of hemopoietic cells. Mlf1 was capable of binding DNA, and microarray analysis revealed that it affected the expression of several genes, including transcription factors. In summary, this study reveals that Mlf1 translocates between nucleus and cytoplasm, associates with a novel hnRNP, and influences gene expression. Myeloid leukemia factor 1 (MLF1)4 is a gene involved in hemopoietic lineage commitment and acute myeloid leukemia (1, 2). The gene was originally identified in a (3;5) translocation associated with acute myeloid leukemia that generated an abnormal fusion with nucleophosmin (NPM), i.e. NPM-MLF1 (1). The t(3;5) is found mainly in the M6 erythroleukemic subtype of acute myeloid leukemia (3). Significantly the fusion protein NPM-MLF1 is almost exclusively nuclear (1).The murine orthologue of MLF1 was isolated independently as hemopoietic lineage switch 7 (Hls7), a gene up-regulated when J2E erythroleukemic cells spontaneously developed a monoblastoid appearance (2, 4). Upon reintroduction into parental J2E cells, Hls7/Mlf1 induced a dramatic phenotypic change as the proerythroblastoid cells now displayed an immature, blast-like appearance (2). Hls7/Mlf1 has also been shown to influence hemopoietic lineage commitment by altering the balance between erythroid and myeloid progenitors (2). In contrast with the nuclear localization of the NPM-MLF1 fusion protein, Mlf1 is located primarily in the cytoplasm with some punctate nuclear staining (1, 2).Apart from a classical 14-3-3 binding site, Mlf1 has no recognizable motifs (1, 2, 5, 6). Therefore, yeast two-hybrid screens have been conducted to identify partner proteins that may elucidate the function of Mlf1. One molecule shown to bind Mlf1 was Mlf1 adaptor molecule (Madm), an adaptor protein involved in nuclear-cytoplasmic shuttling (7). Another Mlf1-binding protein is Mlf1-interacting protein/KSHV latent nuclear antigen-interacting protein (Mlf1IP/KLIP1), a novel nuclear molecule that may function as a transcriptional regulator (8, 9). Interestingly in Drosophila, Mlf1 associates with DNA replication-related element binding factor (DREF) (5), a DNAbinding protein that regulates genes involved in proliferation, including E2f (10). It has been suggested that "the DREF system may occupy an intersection in growth and differentiation signaling pathways" (11).Recently we have shown that Mlf1 interferes with erythropoieti...
Mesothelioma is an almost invariably fatal tumor with chemotherapy extending survival by a few months. One immunotherapeutic strategy is to target dendritic cells (DCs), key antigen-presenting cells involved in antigen presentation, to induce antigen-specific T cell responses. However, DC-targeting will only be effective if DCs are fit-for-purpose, and the functional status of DCs in mesothelioma patients was not clear. We found that mesothelioma patients have significantly decreased numbers of circulating myeloid (m)DC1 cells, mDC2 cells and plasmacytoid (p)DCs relative to healthy age and gender-matched controls. Blood monocytes from patients could not differentiate into immature monocyte-derived DCs (MoDCs), indicated by a significantly reduced ability to process antigen and reduced expression of costimulatory (CD40, CD80 and CD86) and MHC (HLA-DR) molecules, relative to controls. Activation of mesothelioma-derived MoDCs with LPS+/-IFNγ generated partially mature MoDCs, evident by limited upregulation of the maturation marker, CD83, and the costimulatory markers. Attempts to rescue mesothelioma-derived DC function using CD40Ligand(L) also failed, indicated by maintenance of antigen-processing capacity and limited upregulation of CD40, CD83, CD86 and HLA-DR. These data suggest that mesothelioma patients have significant numerical and functional DC defects and that their reduced capacity to process antigen and reduced expression of costimulatory molecules could induce anergized/tolerized T cells. Nonetheless, survival analyses revealed that individuals with mesothelioma and higher than median levels of mDC1s and/or whose MoDCs matured in response to LPS, IFNγ or CD40L lived longer, implying their selection for DC-targeting therapy could be promising especially if combined with another treatment modality.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.