Circadian rhythm regulation in the immune system.

Circadian rhythms are a ubiquitous feature in nearly all living organisms, representing oscillatory patterns with a 24-h cycle that are widespread across various physiological processes. Circadian rhythms regulate a multitude of physiological systems, including the immune system. At the molecular level, most immune cells autonomously express clock-regulating genes, which play critical roles in regulating immune cell functions. These functions encompass migration, phagocytic activity, immune cell metabolism (such as mitochondrial structural function and metabolism), signalling pathway activation, inflammatory responses, innate immune recognition, and adaptive immune processes (including vaccine responses and pathogen clearance). The endogenous circadian clock orchestrates multifaceted rhythmicity within the immune system, optimizing immune surveillance and responsiveness; this bears significant implications for maintaining immune homeostasis and resilience against diseases. This work provides an overview of circadian rhythm regulation within the immune system.

Sulforaphane Attenuates AOM/DSS-Induced Colorectal Tumorigenesis in Mice via Inhibition of Intestinal Inflammation.

Sulforaphane (SFN) is a compound derived from cruciferous plants. It has received considerable attention in recent years due to its effectiveness in cancer prevention and anti-inflammatory properties. The purpose of this study was to evaluate the antitumor potential of sulforaphane on colitis-associated carcinogenesis (CAC) through the establishment of a mouse model with AOM/DSS. First, AOM/DSS and DSS-induced model were established and administered SFN for 10 wk, and then the severity of colitis-associated colon cancer was examined macroscopically and histologically. Subsequently, immune cells and cytokines in the tumor microenvironment (TME) were quantified. Finally, the influence of sulforaphane was also investigated using different colon cell lines. We found that sulforaphane treatment decreased tumor volume, myeloid-derived suppressor cells (MDSC) expansion, the expression of the proinflammatory cytokine IL-1ß, and the level of IL-10 in serum. Also, it enhanced the antitumor activities of CD8+ T cells and significantly reduced tumorigenesis as induced by AOM/DSS. SFN also attenuated intestinal inflammation in DSS-induced chronic colitis by reshaping the inflammatory microenvironment. This work demonstrates that sulforaphane suppresses carcinogenesis-associated intestinal inflammation and prevents AOM/DSS-induced intestinal tumorigenesis and progression.

Feasibility of an exercise-nutrition-psychology integrated rehabilitation model based on mobile health and virtual reality for cancer patients: a single-center, single-arm, prospective phase II study.

OBJECTIVE: Explore the feasibility of a mobile health(mHealth) and virtual reality (VR) based nutrition-exercise-psychology integrated rehabilitation model in Chinese cancer patients. METHODS: We recruited cancer patients in the Oncology department of the Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University from October 2022 to April 2023. The rehabilitation program was provided by a team of medical oncologists, dietitians, psychotherapists, and oncology specialist nurses. Participants received standard anti-cancer therapy and integrated intervention including hospitalized group-based exercise classes, at-home physical activity prescription, behavior change education, oral nutrition supplements, and psychological counseling. An effective intervention course includes two consecutive hospitalization and two periods of home-based rehabilitation (8 weeks). Access the feasibility as well as changes in aspects of physical, nutritional, and psychological status. RESULTS: At the cutoff date of April 2023, the recruitment rate was 75% (123/165). 11.4%patients were lost to follow-up, and 3.25% withdrew halfway. Respectively, the completion rate of nutrition, exercise, and psychology were 85%,55%, and 63%. Nutrition interventions show the highest compliance. The parameters in nutrition, psychology, muscle mass, and quality of life after the rehabilitation showed significant improvements (P < .05). There was no significant statistical difference (P > .05) in handgrip strength and 6-minute walking speed. CONCLUSION: It is feasible to conduct mHealth and VR-based nutrition-exercise-psychology integrated rehabilitation model in Chinese cancer patients. A larger multi-center trial is warranted in the future. TRIAL REGISTRATION: ChiCTR2200065748 Registered 14 November 2022.

Yeast ß-glucan modulates macrophages and improves antitumor NK-cell responses in cancer.

As the largest proportion of myeloid immune cells in tumors, macrophages play an important role in tumor growth and regression according to their different phenotypes, thus reprogramming macrophages has become a new research direction for cancer immunotherapy. Yeast-derived whole ß-glucan particles (WGPs) can induce M0 macrophages to differentiate into M1 macrophages and convert M2 macrophages and tumor-associated macrophages (TAMs) into M1 macrophages. In vitro, studies have confirmed that WGP-treated macrophages increase the activating receptors in natural killer cells (NK cells) and enhance the cytotoxicity of NK cells. The extracellular regulated protein kinases (ERK) signaling pathway is involved in WGP-mediated regulation of the macrophage phenotype. Further in vivo studies show that oral WGP can significantly delay tumor growth, which is related to the increased proportion of macrophages and NK cells, the macrophage phenotype reversal, and the enhancement of NK cell immune function. NK-cell depletion reduces the therapeutic efficacy of WGP in tumor-bearing mice. These findings revealed that in addition to T cells, NK cells also participate in the antitumor process of WGP. It was confirmed that WGP regulates the macrophage phenotype to regulate NK-cell function.

Oral administration of a whole glucan particle (WGP)-based therapeutic cancer vaccine targeting macrophages inhibits tumor growth.

Although therapeutic cancer vaccines have been gaining substantial ground, the development of cancer vaccines is impeded because of the undegradability of delivery systems, ineffective delivery of tumor antigens and weak immunogenicity of adjuvants. Here, we made use of a whole glucan particle (WGP) to encapsulate ovalbumin (OVA), thereby formulating a novel cancer vaccine. Results from in vitro experiments showed that WGP-OVA not only induced the activation of bone marrow-derived macrophages (BMDMs) including driving M0 BMDM polarization to the M1 phenotype, upregulating the costimulatory molecules and inducing the generation of cytokines, but also facilitated antigen presentation. After oral administration of the WGP-OVA formulation to mice with OVA-expressing tumors, these particles can increase tumor-infiltrating OVA-specific CD8+ CTLs and repolarize tumor-associated macrophages (TAMs) toward M1-like phenotype, which led to delayed tumor progression. These findings revealed that WGP could serve as both an antigen delivery system and an adjuvant system for promising cancer vaccines.

Pivotal role of dermal IL-17-producing γδ T cells in skin inflammation.

Interleukin-23 (IL-23) and CD4(+) T helper 17 (Th17) cells are thought to be critical in psoriasis pathogenesis. Here, we report that IL-23 predominantly stimulated dermal γδ T cells to produce IL-17 that led to disease progression. Dermal γδ T cells constitutively expressed the IL-23 receptor (IL-23R) and transcriptional factor RORγt. IL-17 production from dermal γδ T cells was independent of αß T cells. The epidermal hyperplasia and inflammation induced by IL-23 were significantly decreased in T cell receptor δ-deficient (Tcrd(-/-)) and IL-17 receptor-deficient (Il17ra(-/-)) mice but occurred normally in Tcra(-/-) mice. Imiquimod-induced skin pathology was also significantly decreased in Tcrd(-/-) mice. Perhaps further promoting disease progression, IL-23 stimulated dermal γδ T cell expansion. In psoriasis patients, γδ T cells were greatly increased in affected skin and produced large amounts of IL-17. Thus, IL-23-responsive dermal γδ T cells are the major IL-17 producers in the skin and may represent a novel target for the treatment of psoriasis.

Key genes and pathways in tumor-educated dendritic cells by bioinformatical analysis.

Specific tumor microenvironment signaling might prevent the maturation of dendritic cells (DCs) with tolerogenic and immunosuppressive potential accounting for antigen-specific unresponsiveness in the lymphoid organs and in the periphery. In the present study, dendritic cells treated with LLC lung cancer cell or 4T1 breast cancer cell culture supernatants significantly down-regulated the expression of co-stimulatory molecules MHC-II, CD40, CD80, but up-regulated the inhibitory molecule PD-L1/L2, VISTA, and increased the messengerRNA levels of interleukin (IL)-6, arginase I, and IL-10, but decreased tumor necrosis factor-α and IL-12a. RNA was isolated from the dendritic cells with or without tumor supernatant stimulation and RNA sequencing was done. Then the differential expression genes were sorted, the candidate genes were analyzed and pathway enrichment analysis was done, and the associated protein-protein interaction network (PPI) was established. After integrated bioinformatical analysis, 405 (279 up-regulated and 126 down-regulated) consistently differential expression genes were identified. Using gene ontology and pathway analysis, it was found that differential expression genes were mainly enriched in the immune response, cell-cell interaction, hemostasis, and cell surface interactions with the vascular wall. The PPI data demonstrated that 236 nodes were classified with 1072 edges, and the most remarkable three modules involved 53 central node genes associated with cell survival, cell-substrate adhesion, chemotaxis, migration, immune response, and complement receptor mediated signaling pathway. These findings revealed the immune status of dendritic cells in the tumor environment.

Preparation and anti-Raji lymphoma efficacy of a novel pH sensitive and magnetic targeting nanoparticles drug delivery system.

BACKGROUND: Non-Hodgkin's lymphoma (NHL) is a heterogeneous class of cancers that arises in lymph nodes or other lymphatic tissues, which causes many deaths worldwide and its incidence is increasing. METHODS: In this study, a pH-responsive DMSA-Fe3O4 magnetic nanoparticles (MNPs) covalently connect with ADM and As2O3 as a drug delivery system was invented to discuss the anticancer efficacy in non-Hodgkin's lymphoma (NHL) cell line--Raji. RESULTS: Detailedly, according to the chelation of ADM and Fe2+, the release rate of ADM was accelerated in acidic environment, and slowed down/blocked in neutral environment. The inhibitory effect to induce apoptosis of Fe3O4/As2O3+Doxil on Raji cells was obvious compared with that of single-drug group. Furthermore, the expression of Bcl-2 gene in Raji cells was suppressed under the action of MNPs. CONCLUSION: Taken together, the novel pH-responsive MNPs was proven to be a promising synergistic form of magnetic targeted drugs for clinical treatment of human Raji lymphoma.

miR-802 inhibits the proliferation, invasion, and epithelial-mesenchymal transition of glioblastoma multiforme cells by directly targeting SIX4.

It is well known that the sine oculis homeobox 4 (SIX4) expression is very relevant to the progression of multiple cancers. Moreover, we found that miR-802 could directly target the SIX4. However, the precise mechanism of miR-802 in glioblastoma multiforme (GBM) is still unknown. The aim of this study is to investigate the roles of miR-802/SIX4 axis in GBM. Here, our results showed that the SIX4 expression was obviously increased in GBM tissues and cell lines, and the miR-802 level was distinctly decreased. What is more, the SIX4 expression was negatively related to the miR-802 level in GBM tissues. Furthermore, increased miR-802 level evidently restrained the proliferation, invasion, and epithelial-mesenchymal transition (EMT) of GBM cells. Next, we confirmed that miR-802 could directly target SIX4 by using luciferase reporter assay. Besides, the knockdown of SIX4 had the similar effects with miR-802 overexpression on GBM cells. The inhibitory effects of miR-802 mimic were partially blocked by SIX4 overexpression. Altogether, the overexpression of miR-802 restrained cell proliferation, invasion, and EMT of GBM cells via the regulation of SIX4. SIGNIFICANCE OF THE STUDY: An elevated expression of SIX4 has been observed in colorectal cancer and nonsmall cell lung cancer. However, the precise roles of SIX4 in GBM have not been elucidated. Our study for the first time demonstrated that SIX4 level was significantly upregulated in GBM. Additionally, the knockdown of SIX4 inhibited cell growth, invasion, and the EMT of GBM. Moreover, our data suggested a significant negative correlation between miR-802 and SIX4 expression in GBM. MiR-802 suppressed GBM cell proliferation, invasion, and EMT by directly targeting SIX4, which suggested important roles for miR-802/SIX4 axis in the GBM pathogenesis and its potential application in cancer therapy.

Ectopic expression of LAG-3 in non-small-cell lung cancer cells and its clinical significance.

BACKGROUND: Lymphocyte activation gene 3 (LAG-3, also known as CD223) is an immune checkpoint molecule expressed on various types of lymphocytes, and it is mainly involved in maintaining immune homeostasis. However, there are currently no data on LAG-3 expression in non-small-cell lung cancer cells. METHODS: Human lung cancer cells were cultured using conventional methods. The expression of LAG-3 was measured by Western blot and flow cytometry. Between April 2018 and May 2019, we collected 52 surgical specimens of stage I-III non-small-cell lung cancer (NSCLC). Fourteen samples of benign lung tissue lesions were collected as the control group, and the expression levels of LAG-3 in the lung cancer cells and tissue samples were measured via immunohistochemistry. RESULTS: Western blots showed that LAG-3 was expressed in lung cancer cell lines. There was significant difference in the LAG-3 expression levels in the NSCLC cells and benign lung tissue (χ2  = 13.055, P = .0003). The LAG-3 expression level was significantly associated with the NSCLC clinical stage, and LAG-3 expression was significantly higher in stage III patients (P < .05). CONCLUSION: LAG-3 is expressed in NSCLC tumor cells. Furthermore, LAG-3 not only is expressed in tumor-infiltrating lymphocytes in NSCLC patients but also is ectopically expressed in tumor cells and associated with TNM stage.

ß-Glucan induces autophagy in dendritic cells and influences T-cell differentiation.

ß-Glucan has been reported to activate dendritic cells (DCs), and activated DCs, subsequently, promote Th1 and cytotoxic T-lymphocyte priming and differentiation in vitro. However, the mechanism that regulates the immune response of ß-glucan-induced DCs has not been thoroughly elucidated to date. Recent studies have drawn attention to a strong relationship between pathogen-associated molecular patterns (PAMP) recognition and autophagy for the activation of DC function. In this study, we observed that ß-glucan induced the expression of a number of autophagy-related genes and the formation of autophagosomes in DCs. To further investigate whether ß-glucan-induced DC activation and innate cytokine production are associated with autophagy, we utilized 3-MA to block autophagosome formation and accessed the maturation and function of DCs induced by ß-glucan. We found that autophagy-deficient DCs showed downregulated expression of MHC-II and CD80, decreased TNF-α secretion, and reduced production of iNOS upon ß-glucan stimulation. Further examination demonstrated that blockade of autophagy in ß-glucan-induced DCs significantly attenuated IFN-γ production by co-cultured CD4 + T cells and inhibited the proliferation and differentiation of CD4 + T cells. Thus, these data indicate that autophagy in ß-glucan-induced DCs is a crucial mechanism for the maturation of DCs, and it drives innate cytokine production, thereby facilitating adaptive immune responses.

Endovascular Treatment of Patients with Isolated Mesenteric Artery Dissection Aneurysm: Bare Stents Alone Versus Stent Assisted Coiling.

OBJECTIVE: The aim was to evaluate the outcomes of endovascular treatment with bare stents alone versus stent assisted coiling in isolated mesenteric artery dissection (IMAD) aneurysms. METHODS: Patients with an IMAD aneurysm who underwent endovascular stenting between February 2010 and February 2017 at one of three institutions were included in this study. Data regarding technical success, procedure time, symptom resolution, complications, changes in IMAD aneurysm, and stent patency were recorded. RESULTS: A total of 38 patients (35 men) were included, 27 treated with bare stents alone and 11 treated with stent assisted coiling. Technical success was achieved in 100% of patients treated with bare stents and in 81.8% of those treated with stent assisted coiling (p = 0.078). The mean procedure times were 62.6 ± 5.3 min for treatment with bare stents and 116.4 ± 8.4 min for stent assisted coiling (p < 0.001). A total of 23 patients had persistent symptoms before stenting; all symptoms were resolved within 3.0 ± 0.7 days. No procedure related major complications occurred. Over 30.2 ± 18.1 months of follow up, complete resolution of the IMAD aneurysm was achieved in all patients; good stent patency and in stent re-stenosis were achieved in 65.8% and 34.2% patients, respectively. There were no occlusions of the stented arteries. CONCLUSIONS: Bare stents alone and stent assisted coiling have high technical success rates and demonstrate good intermediate patency in patients with an IMAD aneurysm. Bare stents alone may serve as an alternative to stent assisted coiling for the management of IMAD aneurysm.

Factors Associated with Failed Conservative Management in Symptomatic Isolated Mesenteric Artery Dissection.

OBJECTIVE: The aim of this study was to assess factors associated with conservative management failure in patients with symptomatic isolated mesenteric artery dissection. METHODS: Patients with symptomatic isolated mesenteric artery dissection who underwent conservative therapy as first line treatment between February 2010 and May 2018 were included in this retrospective study. Conservative management failure was defined as the persistence or aggravation of symptoms and signs, increasing aneurysmal dilation, or new appearance of a dissecting aneurysm after conservative management. Univariable and multivariable analyses were performed to identify risk factors for failure of conservative management. RESULTS: A total of 123 patients (115 men, 8 women, mean age, 53.7 ± 6.1 years) were included in this study. Conservative management was successful in 89 (72.4%) patients but failed in the remaining 34 (27.6%) patients. Of the 89 for whom conservative management was successful, all of the symptoms were eliminated (n = 81) or relieved (n = 8) within 3.8 ± 0.7 days after conservative management. All of the 34 patients in whom conservative management failed underwent successful endovascular stenting. Failure of conservative management was associated with type II IMADs as defined by the Sakamoto classification (meaning that there is an entry tear, but no re-entry, and still no thrombosis of false lumen, odds ratio: 33.76; 95% confidence interval 8.65-131.85; p < .001) and with ≥90% luminal stenosis (odds ratio 40.70; 95% confidence interval: 3.76-440.07; p < .01). CONCLUSIONS: Conservative management can be used successfully in most patients with symptomatic isolated mesenteric artery dissection. Risk factors for failed conservative treatment were type II IMADs and degree of luminal stenosis ≥90%.

ß-glucan restores tumor-educated dendritic cell maturation to enhance antitumor immune responses.

Tumors can induce the generation and accumulation of immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs) in a tumor microenvironment, contributing to tumor escape from immunological attack. Although dendritic cell-based cancer vaccines can initiate antitumor immune responses, tumor-educated dendritic cells (TEDCs) involved in the tolerance induction have attracted much attention recently. In this study, we investigated the effect of ß-glucan on TEDCs and found that ß-glucan treatment could promote the maturation and migration of TEDCs and that the suppressive function of TEDCs was significantly decreased. Treatment with ß-glucan drastically decreased the levels of regulatory T (Treg) cells but increased the infiltration of macrophages, granulocytes and DCs in tumor masses, thus elicited Th1 differentiation and cytotoxic T-lymphocyte responses and led to a delay in tumor progression. These findings reveal that ß-glucan can inhibit the regulatory function of TEDCs, therefore revealing a novel function for ß-glucan in immunotherapy and suggesting its potential clinical benefit. ß-Glucan directly abrogated tumor-educated dendritic cells-associated immune suppression, promoted Th1 differentiation and cytotoxic T-lymphocyte priming and improved antitumor responses.

MiR-124 inhibits cell proliferation in breast cancer through downregulation of CDK4.

Studies have shown that microRNAs (miRNAs) are involved in the malignant progression of human cancer. However, little is known about the potential role of miRNAs in breast carcinogenesis. miR-124 expression in breast cancer tissue was measured by quantitative real-time PCR (qRT-PCR). Target prediction algorithms and luciferase reporter gene assays were used to investigate the target of miR-124. Breast cancer cells growth was regulated by overexpression or knockdown miR-124. At the end of the study, tumor-bearing mice were tested to confirm the function of miR-124 in breast cancer. In this study, we demonstrated that the expression of miR-124 was significantly downregulated in breast cancer tissues compared with matched adjacent non-neoplastic tissues. We identified and confirmed that cyclin-dependent kinase 4 (CDK4) was a direct target of miR-124. Overexpression of miR-124 suppressed CDK4 protein expression and attenuated cell viability, proliferation, and cell cycle progression in MCF-7 and MDA-MB-435S breast cancer cells in vitro. Overexpression of CDK4 partially rescued the inhibitory effect of miR-124 in the breast cancer cells. Moreover, we found that miR-124 overexpression effectively repressed tumor growth in xenograft animal experiments. Our results demonstrate that miR-124 functions as a growth-suppressive miRNA and plays an important role in inhibiting tumorigenesis by targeting CDK4.

Co-expression of CD40/CD40L on XG1 multiple myeloma cells promotes IL-6 autocrine function.

Multiple myeloma (MM) is characterized by uncontrolled proliferation of malignant plasma cells in the bone marrow and peripheral blood. Here, we found that CD40 and CD40L co-expressed on XG1 MM cells and the coordinated expression of CD40-CD40L was critical for production and autocrine IL-6 in XG1 cells. Furthermore, TNF-α enhanced the expression of both CD40 and CD40L expression on XG1 cells. We also found that persistent CD40L/CD40 signaling was required for the constitutive activation of NF-κB in the cells.

Opposing roles for complement component C5a in tumor progression and the tumor microenvironment.

Promoting complement (C) activation may enhance immunological mechanisms of anti-tumor Abs for tumor destruction. However, C activation components, such as C5a, trigger inflammation, which can promote tumor growth. We addressed the role of C5a on tumor growth by transfecting both human carcinoma and murine lymphoma with mouse C5a. In vitro growth kinetics of C5a, control vector, or parental cells revealed no significant differences. Tumor-bearing mice with C5a-transfected xenografted tumor cells had significantly less tumor burden as compared with control vector tumors. NK cells and macrophages infiltrated C5a-expressing tumors with significantly greater frequency, whereas vascular endothelial growth factor, arginase, and TNF-α production were significantly less. Tumor-bearing mice with high C5a-producing syngeneic lymphoma cells had significantly accelerated tumor progression with more Gr-1+CD11b+ myeloid cells in the spleen and overall decreased CD4+ and CD8+ T cells in the tumor, tumor-draining lymph nodes, and the spleen. In contrast, tumor-bearing mice with low C5a-producing lymphoma cells had a significantly reduced tumor burden with increased IFN-γ-producing CD4+ and CD8+ T cells in the spleen and tumor-draining lymph nodes. These studies suggest concentration of local C5a within the tumor microenvironment is critical in determining its role in tumor progression.

ß-Glucan-A promising immunocyte-targeting drug delivery vehicle: Superiority, applications and future prospects.

Drug delivery technologies that could convert promising therapeutics into successful therapies have been under broad research for many years. Recently, ß-glucans, natural-occurring polysaccharides extracted from many organism species such as yeast, fungi and bacteria, have attracted increasing attention to serve as drug delivery carriers. With their unique structure and innate immunocompetence, ß-glucans are considered as promising carriers for targeting delivery especially when applied in the vaccine construction and oral administration of therapeutic agents. In this review, we focus on three types of ß-glucans applied in the drug delivery system including yeast ß-glucan, Schizophyllan and curdlan, highlighting the benefits of ß-glucan based delivery system. We summarize how ß-glucans as delivery vehicles have aided various therapeutics ranging from macromolecules including proteins, peptides and nucleic acids to small molecular drugs to reach desired cells or organs in terms of loading strategies. We also outline the challenges and future directions for developing the next generation of ß-glucan based delivery systems.

Orally administered yeast-derived ß-glucan alleviates mast cell-dependent airway hyperresponsiveness and inflammation in a murine model of asthma.

BACKGROUND: Particulate ß-glucans (WGP) are natural compounds with regulatory roles in various biological processes, including tumorigenesis and inflammatory diseases such as allergic asthma. However, their impact on mast cells (MCs), contributors to airway hyperresponsiveness (AHR) and inflammation in asthma mice, remains unknown. METHODS: C57BL/6 mice underwent repeated OVA sensitization without alum, followed by Ovalbumin (OVA) challenge. Mice received daily oral administration of WGP (OAW) at doses of 50 or 150 mg/kg before sensitization and challenge. We assessed airway function, lung histopathology, and pulmonary inflammatory cell composition in the airways, as well as proinflammatory cytokines and chemokines in the bronchoalveolar lavage fluid (BALF). RESULTS: The 150 mg/kg OAW treatment mitigated OVA-induced AHR and airway inflammation, evidenced by reduced airway reactivity to aerosolized methacholine (Mch), diminished inflammatory cell infiltration, and goblet cell hyperplasia in lung tissues. Additionally, OAW hindered the recruitment of inflammatory cells, including MCs and eosinophils, in lung tissues and BALF. OAW treatment attenuated proinflammatory tumor necrosis factor (TNF)-α and IL-6 levels in BALF. Notably, OAW significantly downregulated the expression of chemokines CCL3, CCL5, CCL20, CCL22, CXCL9, and CXCL10 in BALF. CONCLUSION: These results highlight OAW's robust anti-inflammatory properties, suggesting potential benefits in treating MC-dependent AHR and allergic inflammation by influencing inflammatory cell infiltration and regulating proinflammatory cytokines and chemokines in the airways.

The engineered agonistic anti-CD40 antibody potentiates the antitumor effects of ß-glucan by resetting TAMs.

Anti-CD40 antibodies (Abs) have been shown to induce antitumor T-cell responses. We reported that the engineered agonistic anti-CD40 Ab (5C11, IgG4 isotype) recognized human CD40 antigen expressed on a human B lymphoblastoid cell line as well as on splenic cells isolated from humanized CD40 mice. Of note, a single high dosage of 5C11 was able to prohibit tumor growth in parallel with an increase in the population of infiltrated CD8+ T cells. Furthermore, the antitumor effects of 5C11 were enhanced in the presence of ß-glucan along with an increase in the population of infiltrated CD8+ T cells. In addition, the numbers of CD86+ TAMs and neutrophils were elevated in the combination of 5C11 and ß-glucan compared with either 5C11 or ß-glucan alone. Furthermore, the abundance of Faecalibaculum, one of the probiotics critical for tumor suppression, was obviously increased in the combination of 5C11 and ß-glucan-treated mice. These data reveal a novel mechanism of tumor suppression upon the combination treatment of 5C11 and ß-glucan and propose that the combination treatment of agonistic anti-human CD40 antibody 5C11 and ß-glucan could be a promising therapeutic strategy for cancer patients.