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The immune activation ability of FimH, an adhesion protein in pili of Escherichia coli (E. coli), has been recently reported. However, studies on the immune activity of PapG, another major pili terminal protein, have not been well explored. In this study, the immune stimulatory effect of purified recombinant PapG was evaluated. PapG treatment promoted dramatic changes in dendritic morphology of the bone marrow-derived dendritic cells (BMDCs) and induced upregulation of co-stimulatory molecule levels, major histocompatibility complex (MHC) I and II expression, and pro-inflammatory cytokine production in BMDCs. To identify the stimulatory receptor of PapG, an in silico study was performed. PapG exhibited strong binding affinity with murine toll-like receptor 2 (TLR2). In addition, PapG-induced activation of splenic DC and its subsets was unsuccessful in TLR2-knock out mice. Combination of PapG and ovalbumin (OVA) elicited OVA-specific T cell proliferation and cytokine production and cytotoxicity that consequently promoted anti-cancer immune responses against OVA-expressing B16 melanoma. Furthermore, PapG treatment induced activation of peripheral blood DCs and its subsets in humans in a TLR2 dependent manner. PapG-stimulated human conventional DC2 promoted syngeneic T cell proliferation and activation. The findings of this study demonstrated that PapG could be a useful immune stimulator for immunotherapy against cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Metastasis and recurrence are the main challenges in cancer treatment. Among various therapeutic approaches, immunotherapy holds promise for preventing metastasis and recurrence. In this study, we evaluated the efficacy of treating primary cancer and blocking metastasis and recurrence with photo-immunotherapeutic nanoparticles, which were synthesized using two types of charged polysaccharides. Codium fragile polysaccharide (CFP), which exhibits immune-stimulating properties and carries a negative charge, was combined with positively charged chitosan to synthesize nanoparticles. Additionally, indocyanine green (ICG), a photosensitizer, was loaded inside these particles and was referred to as chitosan-CFP-ICG (CC-ICG). Murine colon cancer cells (CT-26) internalized CC-ICG, and subsequent 808-nanometer laser irradiation promoted apoptotic/necrotic cell death. Moreover, intratumoral injection of CC-ICG, with 808-nanometer laser irradiation eliminated CT-26 tumors in mice. Rechallenged lung metastases of CT-26 cancer were inhibited by dendritic cell activation-mediated cytotoxic T lymphocyte stimulation in mice cured by CC-ICG. These results demonstrated that CC-ICG is a natural tumor therapeutic with the potential to treat primary tumors and suppress metastasis and recurrence., (© 2024. The Author(s).)

Immune checkpoint inhibitors are showing groundbreaking results in tumor immunotherapy. However, there are cases where treatment efficiency is insufficient due to limitations in immune activity, and various trials to overcome this are being studied. In this study, we investigated the immune activation ability of fucoidan extracted from Durvillaea antarctica (FDA) and whether it can enhance the anti-cancer effects of immune checkpoint inhibitors. FDA treatment resulted in an elevation of co-stimulator and major histocompatibility complex molecule expression, as well as the production of pro-inflammatory cytokines in bone marrow-derived and splenic dendritic cells (DCs). Administration of 50 mg/kg FDA increased the number of splenic CD8 T cells by >1.4-fold compared to PBS administration. Additionally, 50 mg/kg FDA increased the production of IFN-γ in CD4 and CD8 T cells by 4.3-fold and 7.2-fold, respectively, compared to the PBS control. FDA promoted immune cell activation was TLR4 dependent. Furthermore, anti-PD-L1 antibody administration inhibited CT-26 tumor growth by approximately 3-fold compared to the PBS control group, whereas combined treatment with FDA and anti-PD-L1 antibody showed an 8.4-fold tumor growth inhibition effect compared to the PBS control group. Therefore, FDA may be used to enhance the anti-cancer effects of immune checkpoint inhibitors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Nanomedicines hold promise for the treatment of various diseases. However, treating cancer metastasis remains highly challenging. In this study, we synthesized gold nanorods (AuNRs) containing (α-GC), an immune stimulator, for the treatment of primary cancer, metastasis, and recurrence of the cancer. Therefore, the AuNR were coated with lipid bilayers loaded with α-GC (α-LA). Upon irradiation with 808 nm light, α-LA showed a temperature increase. Intra-tumoral injection of α-LA in mice and local irradiation of the 4T1 breast cancer tumor effectively eliminated tumor growth. We found that the presence of α-GC in α-LA activated dendritic cells and T cells in the spleen, which completely blocked the development of lung metastasis. In mice injected with α-LA for primary breast cancer treatment, we observed antigen-specific T cell responses and increased cytotoxicity against 4T1 cells. We conclude that α-LA is promising for the treatment of both primary breast cancer and its metastasis., Competing Interests: Declaration of competing interest All the authors declare they are no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cigarette smoke induces an inflammatory response in the lungs by recruiting inflammatory cells, leading to lung diseases such as lung cancer, chronic obstructive pulmonary disease, and pulmonary fibrosis. Existing inhalation exposure methods for assessing the adverse effects of cigarette smoke require expensive equipment and are labor-intensive. Therefore, we attempted to develop a novel method to assess these adverse effects using intratracheal instillation (ITI) of whole cigarette smoke condensate (WCSC). The WCSC (0, 5, 10, or 20 mg/mL) was administered by ITI once daily for 6 or 12 days using an automatic video instillator. Repeated WCSC ITI increased the lung weight, and monocyte chemoattractant protein-1 (MCP-1), neutrophil, and lymphocyte levels within bronchoalveolar lavage fluid compared to the control. In the histopathological analysis of the lung tissue, a mild inflammatory response was observed in the 6 and 12 days 20 mg/mL WCSC exposure groups. The genome-wide RNA-seq expression patterns revealed that inflammatory and immune response-related genes, such as the chemokine signaling pathway, Th1/Th2 cell differentiation, and cytokine-cytokine receptor interaction, were employed following WCSC exposure. In addition, MCP-1 was time-dependent and increased in the 10 mg/mL exposure group compared to the control group. These results suggested that the WCSC might induce the potential pulmonary inflammatory response. Furthermore, we proposed that ITI may be a rapid and effective method of evaluating the adverse effects of WCSC within a short exposure period (less than 2 weeks), and it can be used to evaluate cigarette inhalation toxicity studies as an alternative method., (© 2023 The Authors. Environmental Toxicology published by Wiley Periodicals LLC.)

Drosophila melanogaster (D. melanogaster) is a promising model biological system. It has a short life cycle and can provide a substantial number of specimens suitable for comprehensive genetic and molecular analyses in a short time. In this study, we investigated the acute inhalation toxicity of methylisothiazolinone (MIT) and chloromethylisothiazolinone (CMIT) in a D. melanogaster model. During exposure, environmental conditions, mass median aerodynamic and geometric standard diameters were measured. After inhalation exposure, the survival rate, climbing ability, and bang sensitivity were measured on days 1, 2, and 7. Notably, the survival rate of flies decreased in an exposure concentration-dependent manner. Climbing ability and bang sensitivity were also altered in the MIT/CMIT group, compared with the negative control group. Overall, these results provide a reliable D. melanogaster model system for inhalation toxicity study.

Introduction: Immune stimulators are used to improve vaccine efficiency; however, they are accompanied by various side effects. In previous studies, we reported that the Escherichia coli adhesion protein, FimH, induces immune activity; however, we did not examine any side effects in colon inflammation., Methods: FimH was administered orally or intraperitoneally ( i.p. ) to mice with dextran sulfate sodium (DSS)-induced colitis, and changes in symptoms were observed. Immune cells infiltrated into the colon after the induction of colon inflammation were analyzed using a flow cytometer. Changes in Th1 and Th17 cells that induce colitis were analyzed. Further, mesenteric lymph node (mLN) dendritic cells (DCs) activated by FimH were identified and isolated to examine their ability to induce T-cell immunity., Results: FimH oral and i.p. administration in C57BL/6 mice did not induce inflammation in the colon; however, DSS-induced colitis was exacerbated by oral and i.p. FimH administration. FimH treatment increased immune cell infiltration in the colon compared to that in DSS colitis. Th1 and Th17 cells, which are directly related to colitis, were increased in the colon by FimH; however, FimH did not directly affect the differentiation of these T cells. FimH upregulated the CD11b + CD103 - DC activity in the mLNs, which produced the signature cytokines required for Th1 and Th17. In addition, isolated CD11b + CD103 - DCs, after stimulation with FimH, directly induced Th1 and Th17 differentiation in a co-culture of CD4 T cells., Conclusion: This study demonstrated the side effects of FimH and indicated that the use of FimH can aggravate the disease in patients with colitis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhang, An, Kim, Park, Lee and Jin.)

Multi-organ inflammatory diseases are one of the most serious autoimmune diseases worldwide. The regulation of immune responses by immune checkpoint proteins influences the development and treatment of cancer and autoimmune diseases. In this study, recombinant murine PD-L1 (rmPD-L1) was used for controlling T cell immunity to treat multi-organ inflammation. To enhance the immunosuppressive effect, we incorporated methotrexate, an anti-inflammatory drug, into hybrid nanoparticles (HNPs) and decorated the surface of HNPs with rmPD-L1 to produce immunosuppressive HNPs (IsHNPs). IsHNP treatment effectively targeted PD-1-expressing CD4 and CD8 T cells in the splenocytes; additionally, it promoted the production of Foxp3-expressing regulatory T cells, which suppressed the differentiation of helper T cells. IsHNP treatment also inhibited anti-CD3 antibody-mediated activation of CD4 and CD8 T cells in mice in vivo. This treatment protected mice from multi-organ inflammation induced by the adoptive transfer of naïve T cells to recombination-activating gene 1 knockout mice. The results of this study imply the therapeutic potential of IsHNPs in the treatment of multi-organ inflammation and other inflammatory diseases., Competing Interests: Declaration of competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Porphyran is known to inhibit immune cell function. Previously, porphyran was shown to prevent lipopolysaccharide-induced sepsis in mice. However, studies on the inhibitory effects of porphyran during colitis are currently lacking. In this study, we evaluated the effects of Pyropia yezoensis-derived porphyran on dextran sodium sulfate (DSS)-induced acute and chronic colitis. The oral or intraperitoneal administration of porphyran inhibited the progression of DSS-induced colitis in mice, with the former also preventing immune cell infiltration in the colon. The levels of intracellular interferon-γ and interleukin-17 in T cells decreased when porphyran was administered orally. Porphyran inhibited T cell activation by suppressing dendritic cells (DCs) and macrophages. Porphyran prevented pathogen-associated molecular pattern and damage-associated molecular pattern-dependent DC and macrophage activation. Finally, porphyran attenuated chronic colitis caused via the long-term administration of DSS. These findings indicate that the oral administration of porphyran can inhibit DSS-induced colitis by suppressing DC and macrophage activation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Effective cancer therapy aims to treat not only primary tumors but also metastatic and recurrent cancer. Immune check point blockade-mediated immunotherapy showed promising effect against tumors; however, it still has a limited effect in metastatic or recurrent cancer. Here, we extracted recombinant murine programmed death-1 (rmPD-1) proteins. The extracted rmPD-1 effectively bound to CT-26 and 4T1 cells expressing PD-L1 and PD-L2. The rmPD-1 did not alter the activation of dendritic cells (DCs); however, rmPD-1 promoted T cell-mediated anti-cancer immunity against CT-26 tumors in mice. Moreover, rmPD-1 decorated thermal responsive hybrid nanoparticles (piHNPs) promoted apoptotic and necrotic cell death of CT-26 cells in response to laser irradiation at 808 nm consequently, it promoted anti-tumor effects against the 1st challenged CT-26 tumors in mice. In addition, piHNP-mediated cured mice from 1st challenged CT-26 was also prevented the 2nd challenged lung metastatic tumor growth, which was dependent of cancer antigen-specific memory T cell immunity. It was also confirmed that the lung metastatic growth of 2nd challenged 4T1 breast cancer was also prevented in cured mice from 1st challenged 4T1 by piHNP. Thus, these data demonstrate that rmPD-1 functions as an immune checkpoint blockade for the treatment of tumors, and piHNPs could be a novel therapeutic agent for preventing cancer metastasis and recurrence., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Laminaria japonica is a brown alga and is composed primarily of polysaccharides. Fucoidan and laminarin are the major polysaccharides of L. japonica and exhibit biological activities, including immune modulation and anti-coagulant and antioxidant effects in animals and humans. In this study, we evaluated the ability of fucoidan and laminarin from L. japonica to induce immune cell activation and anti-cancer immunity, which has not yet been studied. The injection of fucoidan to mice promoted the upregulation of major histocompatibility complex and surface activation molecules in splenic dendritic cell subsets, whereas laminarin showed a weaker immune activation ability. In addition, fucoidan treatment elicited inflammatory cytokine production; however, laminarin did not induce the production of these cytokines. Regarding cytotoxic cell activities, fucoidan induced the activation of lymphocytes, including natural killer and T cells, whereas laminarin did not induce cell activation. Finally, fucoidan enhanced the anticancer efficacy of anti-programmed Death-Ligand 1 (PD-L1) antibody against Lewis lung carcinoma, whereas laminarin did not promote the cancer inhibition effect of anti-PD-L1 antibody. Thus, these data suggest that fucoidan from L. japonica can be used as an immune stimulatory molecule to enhance the anticancer activities of immune checkpoint inhibitors., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Fucoidan is a sulfated polysaccharide, derived from various marine brown seaweeds, that has immunomodulatory effects. In this study, we analyzed the effects of five different fucoidans, which were extracted from Ascophyllum nodosum, Undaria pinnatifida, Macrocystis pyrifera, Fucus vesiculosus, and Ecklonia cava, on natural killer (NK) cell activation in mice. Among these, E. cava fucoidan (ECF) promoted an increase in the number of NK cells in the spleen and had the strongest effect on the activation of NK cells. Additionally, we observed that DC stimulation was required for NK cell activation and that ECF had the most potent effect on splenic dendritic cells (DC). Finally, ECF treatment effectively prevented infiltration of CT-26 carcinoma cells in the lungs of BALB/c mice in an NK cell dependent manner. Collectively, these results suggest that ECF could be a suitable candidate for enhancing NK cell-mediated anti-cancer immunity., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Advanced cancer therapy is targeted at primary tumors and also recurrent or metastatic cancers. Combinational cancer treatment has recently shown high efficiency against recurrent and metastatic cancers. In this study, we synthesized a thermal responsive hybrid nanoparticle (TRH) containing FimH, an immune stimulatory recombinant protein, for the induction of a combination of photothermal therapy (PTT) and immunotherapy against cancer and its metastasis., Methods: The hybrid nanoparticle was incorporated with a near-infrared (NIR) absorbent, indocyanine green, and decorated with FimH on its surface to form F-TRH. F-TRH was evaluated for its anticancer and antimetastatic effects against CT-26 carcinoma in mice by combining PTT and immunotherapy., Results: NIR laser irradiation elicited an elevation of temperature in F-TRH, which induced apoptosis in CT-26 carcinoma cells in vitro. In addition, F-TRH and NIR laser irradiation promoted photothermal-mediated therapeutic effects against CT-26 and 4T1 tumors in mice. The release of FimH from F-TRH in response to elevated temperature and apoptotic bodies of cancer cells via PTT elicited dendritic cell-mediated cancer antigen-specific T-cell responses, which subsequently inhibited the second challenge of CT-26 and 4T1 cell growth in the lung., Conclusions: These data demonstrate the potential use of F-TRH for immuno-photothermal therapy against cancer and its recurrence and metastasis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Brown seaweed is an important source of fucoidan, which displays immunomodulatory effects by activating various immune cells. However, these effects of fucoidans from various sources of brown seaweed have not yet been explored in human blood dendritic cells. We studied fucoidans extracted from Ecklonia cava, Macrocystis pyrifera, Undaria pinnatifida, and Fucus vesiculosus for their effects on human monocyte-derived dendritic cells (MODC) and human peripheral blood DC (PBDC) activation. Ecklonia cava fucoidan (ECF) strongly upregulated co-stimulatory molecules, major histocompatibility complex class I and II, and the production of proinflammatory cytokines in MODCs and PBDCs compared to those by the other three fucoidans. Moreover, ECF elicited the strongest effect in the induction of syngeneic T cell proliferation and IFN-γ production compared to those of other fucoidans. These results suggest that ECF could be a suitable candidate molecule for enhancing immune activation in humans compared to that with the other three fucoidans., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Astragalus membranaceus (A. membranaceus) is a widely used traditional herb in China and Korea. A. membranaceus polysaccharides (AMP), which make up a major part of the root extract, have been shown to modulate immune modulations, especially activation of bone marrow-derived dendritic cells (BMDCs) and T cells. However, the immune stimulatory effect of AMP in the mouse in vivo and human peripheral blood DCs (PBDCs) has not been well investigated. In this study, we found that intravenous (i.v.) injection of AMP in C57BL/6 mice induced remarkable elevations in co-stimulatory and MHC class I and II molecule levels in the splenic DCs and its subsets. The stimulatory effect of DCs by AMP was elevated 6 h after treatment, which rapidly decreased 18 h after injection. Furthermore, AMP promoted intracellular production of pro-inflammatory cytokines in spleen DC subsets, which contributed elevation of serum cytokine levels. Finally, the AMP promoted PBDC activation. Thus, these results demonstrate that AMP can be used as an immune stimulatory molecules in human and mouse., (Copyright © 2021 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.)

Natural polysaccharides exhibit beneficial immune modulatory effects, including immune stimulatory and anti-cancer activities. In this study, we examined the effect of Codium fragile polysaccharide (CFP) on natural killer (NK) cell activation, and its effect on tumor-bearing mice. Intravenous CFP treatment of C57BL/6 mice resulted in the upregulation of CD69, which is a marker associated with NK cell activation. In addition, intracellular levels of interferon (IFN)-γ and the cytotoxic mediators perforin and granzyme B were markedly increased in response to the CFP treatment of splenic NK cells. IFN-γ production by NK cells was directly induced by CFP, whereas the upregulation of CD69 and cytotoxic mediators required IL-12. Finally, intraperitoneal treatment with CFP prevented CT-26 (murine carcinoma) tumor cell infiltration in the lungs, without significantly reducing the body weight. In addition, treatment with CFP prevented B16 melanoma cell infiltration in the lung of C57BL/6 mice. Moreover, the anti-tumor effect was diminished by the depletion of NK cells. Therefore, these data suggest that CFP may be used as an NK cell stimulator to produce a phenomenon that contributes to anti-cancer immunity.

Natural polysaccharides exhibit an immunostimulatory effect with low toxicity in humans and animals. It has shown that polysaccharide extracted from Codium fragile (CFP) induces anti-cancer immunity by dendritic cell (DC) activation, while the effect of CFP has not examined in the human immune cells. In this study, we found that CFP promoted the upregulation of CD80, CD83 and CD86 and major histocompatibility complex (MHC) class I and II in human monocyte-derived dendritic cells (MDDCs). In addition, CFP induced the production of proinflammatory cytokines in MDDCs. Moreover, CFP directly induced the activation of Blood Dendritic Cell Antigen (BDCA)1 + and BDCA3 + subsets of human peripheral blood DCs (PBDCs). The CFP-stimulated BDCA1 + PBDCs further promoted activation and proliferation of syngeneic CD4 T cells. The CFP-activated BDCA3 + PBDCs activated syngeneic CD8 T cells, which produced cytotoxic mediators, namely, cytotoxic T lymphocytes. These results suggest that CFP may be a candidate molecule for enhancing immune activation in humans.

(1) Background: Aluminum oxide (Al 2 O 3 ) ceramic is one of the materials used for artificial joints, and it has been known that their fine particles (FPs) are provided by the wear of the ceramic. Al 2 O 3 FPs have been shown to induce macrophage activation in vitro; however, the inflammatory effect in vivo has not been studied. (2) Methods: We examined the in vivo effect of Al 2 O 3 FPs on the innate and adaptive immune cells in the mice. (3) Results: Al 2 O 3 FPs promoted the activation of spleen macrophages; however, conventional dendritic cells (cDCs), plasmacytoid DCs (pDCs), and natural killer (NK) cells were not activated. In addition, increases in the CD4 and CD8 T cells was induced in the spleens of the mice treated with Al 2 O 3 FPs, which differentiated into interferon-gamma (IFN-γ)-producing helper T1 (Th1) and cytotoxic T1 (Tc1) cells. Finally, the injection of Al 2 O 3 FPs exacerbated dextran sulfate sodium (DSS)-induced inflammation in the colon, mediated by activated and increased number of CD4 and CD8 T cells. (4) Conclusions: These data demonstrate that FPs of Al 2 O 3 ceramic may contribute to the exacerbation of inflammatory diseases in the patients.

Fucoidan is known to exert immunomodulatory effects in animals and humans. Here, we extracted fucoidan from Ecklonia cava (ECF) and evaluated its immunostimulatory and anticancer activities in mice. Treatment with ECF resulted in the activation of bone marrow-derived dendritic cells (BMDCs) in vitro and splenic DCs in vivo. Moreover, the combination of ECF and ovalbumin (OVA) promoted OVA-specific T cell proliferation and cytokine production, which consequently suppressed B16-OVA tumor growth in vivo. The combination treatment with ECF and carcinoma self-antigen resulted in the inhibition of the growth of CT-26 carcinoma in mice through carcinoma antigen-specific immunity. Thus, ECF could function as an adjuvant for the induction of anticancer immunity., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Natural polysaccharides have shown immune modulatory effects with low toxicity in both animal and human models. A previous study has shown that the polysaccharide from Codium fragile (CFP) promotes natural killer (NK) cell activation in mice. Since NK cell activation is mediated by dendritic cells (DCs), we examined the effect of CFP on DC activation and evaluated the subsequent induction of anti-cancer immunity in a murine model. Treatment with CFP induced activation of bone marrow-derived dendritic cells (BMDCs). Moreover, subcutaneous injection of CFP promoted the activation of spleen and lymph node DCs in vivo . CFP also induced activation of DCs in tumor-bearing mice, and combination treatment with CFP and ovalbumin (OVA) promoted OVA-specific T cell activation, which consequently promoted infiltration of IFN-γ-and TNF-α-producing OT-1 and OT-II cells into the tumors. Moreover, combination treatment using CFP and cancer self-antigen efficiently inhibited B16 tumor growth in the mouse model. Treatment with CFP also enhanced anti-PD-L1 antibody mediated anti-cancer immunity in the CT-26 carcinoma-bearing BALB/c mice. Taken together these data suggest that CFP may function as an adjuvant in the treatment of cancer by enhancing immune activation., Abbreviations: CFP: Codium fragile polysaccharide; NK: natural killer; IFN: interferon; TNF: tumor necrosis factor; IL: interleukin; tdLN: tumor draining lymph node; BMDC: bone marrow-derived dendritic cell; OVA: ovalbumin; Ab: antibody; Ag: antigen; DC: dendritic cell; CTL: cytotoxic T lymphocyte; APC: antigen-presenting cell; pDC: plasmacytoid dendritic cell; mDC: myeloid dendritic cell; MHC: major histocompatibility complex; CR3: complement receptor type 3; TLR: Toll-like receptor; LPS: lipopolysaccharide; SP: sulfated polysaccharide; TRP2: tyrosinase-related protein 2; SR-A: scavenger receptor-A., (© 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Induction of antigen-specific immune activation by the maturation of dendritic cells (DCs) is a strategy used for cancer immunotherapy. In this study, we find that FimH, which is an Escherichia coli adhesion portion, induces toll-like receptor 4-dependent and myeloid differentiation protein 2-independent DC maturation in mice in vivo. A combined treatment regimen with FimH and antigen promotes antigen-specific immune activation, including proliferation of T cells, production of IFN-γ and TNF-α, and infiltration of effector T cells into tumors, which consequently inhibits tumor growth in mice in vivo against melanoma and carcinoma. In addition, combined therapeutic treatment of anti-PD-L1 antibodies and FimH treatment efficiently inhibits CT26 tumor growth in BALB/c mice. Finally, FimH promotes human peripheral blood DC activation and syngeneic T-cell proliferation and activation. Taken together, these findings demonstrate that FimH can be a useful adjuvant for cancer immunotherapy.

We previously demonstrated that porphyran, a sulfated polysaccharide extracted from Pyropia yezoensis, shows protective effects on LPS-induced septic shock in the mouse. However, the immune cell-mediated inhibitory effect of porphyran in LPS-induced activation of immune cells has not been well investigated. In this study, we found that treatment of porphyran suppressed LPS-induced upregulation of costimulatory molecule and C-C chemokine receptor type 7 (CCR7) expression in bone marrow-derived dendritic cells (BMDCs) in vitro and spleen DCs in vivo. Moreover, the LPS-induced expression of IL-6, IL-12, and TNF-α in the culture medium of BMDCs and serum dose-dependently decreased by porphyran treatment, which contributed to the inhibition of the intracellular cytokine production in spleen DCs. In addition, LPS-induced differentiation of helper T1 (Th1) and cytotoxic T1 (Tc1) cells was effectively suppressed by porphyran treatment in mice. The inhibitory effect of porphyran in LPS-induced immune activation was mediated by competitive binding of porphyran with LPS in spleen DCs. Thus, these results suggest that porphyran is a promising potential therapeutic agent in endotoxin-mediated inflammatory disease and septic shock., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Efficient cancer therapy is sought not only for primary tumor treatment but also for the prevention of metastatic cancer growth. Immunotherapy has been shown to prevent cancer metastasis by inducing antigen-specific immune responses. Indocyanine green (ICG) has a peak spectral absorption at about 800 nm, which makes it a photothermal reagent for direct treatment of solid tumors by photothermal therapy (PTT). Since PTT alone cannot fully induce antigen-specific immune response for prevention of cancer metastasis, the combination of PTT and immunotherapy has been developed as a new strategy of cancer treatment., Methods: Thermal responsive liposomes (TRL) were synthesized by incorporating ICG into the lipid bilayer and encapsulating the water-soluble immune stimulatory molecule polyinosinic:polycytidylic acid (poly I:C) in the hydrophilic core. The poly I:C- and ICG-containing TRLs (piTRLs) were analyzed according to size, and their photothermal effect was evaluated following laser irradiation at 808 nm. Moreover, the temperature-dependent release of poly I:C was also measured. For cancer therapy, CT-26 (carcinoma) and B16 (melanoma) cells were subcutaneously inoculated to build the 1st transplanted tumor in BALB/c and C57BL/6 mice, respectively. These mice received a 2nd transplantation with the same cancer cells by intravenous inoculation, for evaluation of the anti-metastatic effects of the liposomes after PTT., Results: Near-infrared (NIR) laser irradiation increased the temperature of piTRLs and effectively released poly I:C from the liposomes. The increased temperature induced a photothermal effect, which promoted cancer cell apoptosis and dissolution of the 1st transplanted tumor. Moreover, the released poly I:C from the piTRL induced activation of dendritic cells (DCs) in tumor draining lymph node (tdLN). Cancer cell apoptosis and DC-activation-mediated cancer antigen-specific immune responses further prevented growth of lung metastatic cancer developed following intravenous transplantation of cancer cells., Conclusion: These results demonstrated the potential usage of a piTRL with laser irradiation for immuno-photothermal therapy against various types of cancer and their metastases.

In our previous study, we showed that ascophyllan purified from Ascophyllum nodosum treatment promotes mouse dendritic cell (DC) activation in vivo, further induces an antigen-specific immune response and has anticancer effects in mice. However, the effect of ascophyllan has not been studied in human immune cells, specifically in terms of activation of human monocyte-derived DCs (MDDCs) and human peripheral blood DCs (PBDCs). We found that the treatment with ascophyllan induced morphological changes in MDDCs and upregulated co-stimulatory molecules and major histocompatibility complex class I (MHC I) and MHC II expression. In addition, pro-inflammatory cytokine levels in culture medium was also dramatically increased following ascophyllan treatment of MDDCs. Moreover, ascophyllan promoted phosphorylation of ERK, p38 and JNK signaling pathways, and inhibition of p38 almost completely suppressed the ascophyllan-induced activation of MDDCs. Finally, treatment with ascophyllan induced activation of BDCA1 and BDCA3 PBDCs. Thus, these data suggest that ascophyllan could be used as an immune stimulator in humans.