Antibody production is a metabolically demanding process that is regulated by gut microbiota, but the microbial products supporting B cell responses remain incompletely identified. We report that ...short-chain fatty acids (SCFAs), produced by gut microbiota as fermentation products of dietary fiber, support host antibody responses. In B cells, SCFAs increase acetyl-CoA and regulate metabolic sensors to increase oxidative phosphorylation, glycolysis, and fatty acid synthesis, which produce energy and building blocks supporting antibody production. In parallel, SCFAs control gene expression to express molecules necessary for plasma B cell differentiation. Mice with low SCFA production due to reduced dietary fiber consumption or microbial insufficiency are defective in homeostatic and pathogen-specific antibody responses, resulting in greater pathogen susceptibility. However, SCFA or dietary fiber intake restores this immune deficiency. This B cell-helping function of SCFAs is detected from the intestines to systemic tissues and conserved among mouse and human B cells, highlighting its importance.
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•Short-chain fatty acids (SCFAs) produced by gut microbiota promote antibody responses•SCFAs activate B cell metabolism for production of energy and building blocks•SCFAs control gene expression for plasma B cell differentiation•SCFAs boost antibody responses during infection, decreasing susceptibility to pathogens
Kim et al. demonstrate that short-chain fatty acids (SCFAs), produced by the gut microbiota as fermentation products of dietary fiber, support host antibody responses by regulating gene expression and enhancing cellular metabolism and plasma B cell differentiation. SCFAs boost mucosal and systemic antibody responses during steady state and infection.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Tumour cell phagocytosis by antigen presenting cells (APCs) is critical to the generation of antitumour immunity. However, cancer cells can evade phagocytosis by upregulating anti-phagocytosis ...molecule CD47. Here, we show that CD47 blockade alone is inefficient in stimulating glioma cell phagocytosis. However, combining CD47 blockade with temozolomide results in a significant pro-phagocytosis effect due to the latter's ability to induce endoplasmic reticulum stress response. Increased tumour cell phagocytosis subsequently enhances antigen cross-presentation and activation of cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) in APCs, resulting in more efficient T cell priming. This bridging of innate and adaptive responses inhibits glioma growth, but also activates immune checkpoint. Sequential administration of an anti-PD1 antibody overcomes this potential adaptive resistance. Together, these findings reveal a dynamic relationship between innate and adaptive immune regulation in tumours and support further investigation of phagocytosis modulation as a strategy to enhance cancer immunotherapy responses.
Tumour-targeted immunotherapy offers the unique advantage of specific tumouricidal effects with reduced immune-associated toxicity. However, existing platforms suffer from low potency, inability to ...generate long-term immune memory and decreased activities against tumour-cell subpopulations with low targeting receptor levels. Here we adopted a modular design approach that uses colloidal nanoparticles as substrates to create a multivalent bi-specific nanobioconjugate engager (mBiNE) to promote selective, immune-mediated eradication of cancer cells. By simultaneously targeting the human epidermal growth factor receptor 2 (HER2) expressed by cancer cells and pro-phagocytosis signalling mediated by calreticulin, the mBiNE stimulated HER2-targeted phagocytosis and produced durable antitumour immune responses against HER2-expressing tumours. Interestingly, although the initial immune activation mediated by the mBiNE was receptor dependent, the subsequent antitumour immunity also generated protective effects against tumour-cell populations that lacked the HER2 receptor. Thus, the mBiNE represents a new targeted, nanomaterial-immunotherapy platform to stimulate innate and adaptive immunity and promote a universal antitumour response.
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IJS, NUK, SBMB, UL, UM, UPUK
Nanomedicine is a burgeoning industry but an understanding of the interaction of nanomaterials with the immune system is critical for clinical translation. Macrophages play a fundamental role in the ...immune system by engulfing foreign particulates such as nanoparticles. When activated, macrophages form distinct phenotypic populations with unique immune functions, however the mechanism by which these polarized macrophages react to nanoparticles is unclear. Furthermore, strategies to selectively evade activated macrophage subpopulations are lacking. Here we demonstrate that stimulated macrophages possess higher phagocytic activities and that classically activated (M1) macrophages exhibit greater phagocytic capacity than alternatively activated (M2) macrophages. We show that modification of nanoparticles with polyethylene-glycol results in decreased clearance by all macrophage phenotypes, but importantly, coating nanoparticles with CD47 preferentially lowers phagocytic activity by the M1 phenotype. These results suggest that bio-inspired nanoparticle surface design may enable evasion of specific components of the immune system and provide a rational approach for developing immune tolerant nanomedicines.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Designing nanomedicine for immuno-oncology Jiang, Wen; von Roemeling, Christina A.; Chen, Yuanxin ...
Nature biomedical engineering,
02/2017, Volume:
1, Issue:
2
Journal Article
Peer reviewed
Two major obstacles facing cancer nanomedicine are the tendency of nanoparticles to be taken up by normal tissues and organs and the nanoparticles' inability to efficiently penetrate solid tumours. ...Although substantial efforts have been made to improve the intratumoural delivery of nanotherapeutics, many strategies have failed to produce meaningful clinical benefits. Recent advances in the field of immuno-oncology have led to drugs that boost the host's own immune system to fight cancer. In contrast to conventional therapies, which often target cancer cells, immunotherapies stimulate immune cells in ways that promote their recognition and the eradication of tumours. In this Perspective, we posit that this approach represents a new framework for cancer nanomedicine, and that immune-targeted nanomedicines could generate tumouricidal effects without the need to overcome the pathophysiological barriers that are intrinsic to the tumour microenvironment and that hinder nanoparticle delivery. The rational design of new immuno-oncology nanomedicines provides opportunities for developing the next generation of nanotherapeutics for cancer patients.Drawing from recent successes in cancer immunotherapy, this Perspective discusses that effective cancer-nanomedicine therapies can be designed to prime antitumour immunity far from the site of disease.
A major challenge in the development of cancer nanomedicine is the inability for nanomaterials to efficiently penetrate and deliver therapeutic agents into solid tumors. Previous studies have shown ...that tumor vasculature and extracellular matrix regulate the transvascular and interstitial transport of nanoparticles, both critical for successfully delivering nanomedicine into solid tumors. Within the malignant tumor microenvironment, blood vessels are morphologically abnormal and functionally exhibit substantial permeability. Furthermore, the tumor extracellular matrix (ECM), unlike that of the normal tissue parenchyma, is densely packed with collagen. These pathophysiological properties greatly impede intratumoral delivery of nanomaterials. By using an antivascular endothelial growth factor receptor antibody, DC101, and an antitransforming growth factor β1 (TGF‐β1) antibody, normalization of the tumor vasculature and ECM is achieved, respectively, in a syngeneic murine glioma model. This normalization effect results in a more organized vascular network, improves tissue perfusion, and reduces collagen density, all of which contribute to enhanced nanoparticle delivery and distribution within tumors. These findings suggest that combined vascular and ECM normalization strategies can be used to remodel the tumor microenvironment and improve nanomedicine delivery into solid tumors, which has significant implications for developing more effective combinational therapeutic strategies using cancer nanomedicine.
Simultaneous normalization of tumor vasculature and extracellular matrix using antivascular endothelial growth factor receptor and antitransforming growth factor antibodies enable more efficient delivery of nanoparticles into solid tumors. The tumor microenvironment normalization strategy is expected to provide new strategies to improve the therapeutic efficacy of cancer nanomedicines.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract
INTRODUCTION:
A major challenge in cancer nanotechnology is the efficient delivery of nanomedicines into solid tumors. Nanomedicine relies on a functional vascular network and minimal tissue ...resistance to achieve homogeneous transport and distribution in solid tumor via convection- and diffusion-based mechanisms. This is especially true for brain tumors, where the presence of specialized blood-brain barrier further impedes transport of nanomedicine from the systemic circulation into the central nervous system. Unlike blood vessels within healthy tissues, tumor vessels are often morphologically pathological and functionally impaired, due to an imbalance of pro- and antiangiogenic growth factor production within the tumor microenvironment. Furthermore, within the tumor stroma, excessive and heterogeneous productions of collagen and other matrix proteins further restrict nanomedicine distribution.
METHODS:
We characterized in real-time, perfusion and diffusion parameters of luminescent nanoparticles using syngeneic GL261 and the spontaneous RCAS-hPDGFb-HA/nestin Tv-a; Ink4a/Arf−/− brain tumor model with multiphoton imaging in vivo.
RESULTS:
We demonstrate that tumor vasculature exhibits increased permeability and decreased perfusion capacity compared with normal vessels. As a result, transport of nanomedicine across the vessel wall into the tumor stroma is strongly dependent on particle size and surface polarity. Intratumoral mapping of nanomedicine distribution reveals that once gaining entry into tumors, nanoparticles often experience perivascular clumping and are unable to reach tumor tissue beyond 20 µm from the nearest vessels. Finally, with therapeutic modulation of the tumor microenvironment using anti-VEGFr or anti-TGFβ1 antibody treatments to remodel the tumor vasculature and collagen matrix, respectively, we show that tumors begin to exhibit improved tissue perfusion with improved delivery and distribution with nanomedicine into the tumor interstitium.
CONCLUSION:
The successful implementation of this combined therapeutic approach can have significant implications in developing effective targeted nanomedicines for brain tumors. These findings suggest that optimized delivery of nanomedicine for brain tumors may be possible through the modulation of both the tumor vasculature and extracellular matrix.
Abstract Tuberculosis (TB) remains a major infectious disease worldwide despite chemotherapy and BCG vaccine. The efficacy of the current TB vaccine BCG varies from 0 to 80%. New vaccines that have ...better protection than BCG or have the capability to boost BCG-primed immunity are urgently needed. We have previously constructed a fusion protein Ag85B-MPT64190–198 -Mtb8.4 (AMM). In this study, we investigated the immunogenicity of the fusion protein AMM in a novel adjuvant of dimethyl-dioctyldecyl ammonium bromide and BCG polysaccharide nucleic acid (DDA–BCG PSN), and its capacity to boost BCG-primed immunity. The anti-Ag85B antibodies IgG1 and IgG2a were determined using ELISA and the number of spleen cells secreting IFN-γ was determined by ELISPOT. In addition, the ability of the subunit vaccine AMM to boost BCG-primed immunity against Mycobacterium tuberculosis was analyzed. The fusion protein AMM induced more effective humoral and cell-mediated immune responses in mice than Ag85B alone. Mice primed with BCG vaccination followed by boosting with AMM produced a stronger immune response and afforded a better protection against M. tuberculosis infection than mice immunized with BCG alone or BCG priming followed by boosting with Ag85B. These findings suggest that AMM is a promising candidate subunit vaccine to enhance the protective efficiency of BCG.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
In this study, the protective efficacy of a novel recombinant BCG strain co-expressing Ag85B and Rv3425 against Mycobacterium tuberculosis H37Rv was evaluated in mice. This rBCG::Ag85B-Rv3425 strain ...could provide similar or even better protective efficacy against M. tuberculosis challenge compared with BCG, as shown by no weight loss, significantly reduced lung:body weight ratios and lung bacteria load only at early time of infection. The results suggest that rBCG::Ag85B-Rv3425 could be a potential tuberculosis vaccine candidate for further study.
ABSTRACT
Subtractive DNA hybridization of pathogenic M. bovis and BCG, and comparative genome‐wide DNA microarray analysis of M. tuberculosis H37Rv and BCG identified several RD, designated as RD1 to ...RD16, between M. tuberculosis and M. bovis on the one hand and BCG on the other. These regions cover 108 ORF of M. tuberculosis H37Rv, and are deleted from all 13 BCG sub‐strains currently used as anti‐tuberculosis vaccines in different parts of the world. In this study, we evaluated cellular and humoral immune response in C57BL/6 mice immunized with the PPE protein Rv3425, encoded by an ORF found in RD11 of M. tuberculosis. Rv3425 protein induced an increased Th1/Th2 type immune response in mice, characterized by an elevated concentration of IFN‐γ in antigen stimulated splenocyte culture and a strong IgG1 antibody response. These results provide evidence on the immunogenicity of the PPE protein Rv3425 which, together with its reported immunodominant characteristics, imply that it may be a candidate for development of a vaccine for the control of TB.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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