Nanoparticle cancer vaccines:Design considerations and recent advances

Vaccines therapeutics manipulate host’s immune system and have broad potential for cancer prevention and treatment.However,due to poor immunogenicity and limited safety,fewer cancer vaccines have been successful in clinical trials.Over the past decades,nanotechnology has been exploited to deliver cancer vaccines,eliciting longlasting and effective immune responses.Compared to traditional vaccines,cancer vaccines delivered by nanomaterials can be tuned towards desired immune profiles by(1)optimizing the physicochemical properties of the nanomaterial carriers,(2)modifying the nanomaterials with targeting molecules,or(3)co-encapsulating with immunostimulators.In order to develop vaccines with desired immunogenicity,a thorough understanding of parameters that affect immune responses is required.Herein,we discussed the effects of physicochemical properties on antigen presentation and immune response,including but not limited to size,particle rigidity,intrinsic immunogenicity.Furthermore,we provided a detailed overview of recent preclinical and clinical advances in nanotechnology for cancer vaccines,and considerations for future directions in advancing the vaccine platform to widespread anti-cancer applications.

Engineering humanized mice for improved hematopoietic reconstitution

Humanized mice are immunodeficient animals engrafted with human hematopoietic stem cells that give rise to various lineages of human blood cells throughout the life of the mouse. This article reviews recent advances in the generation of humanized mice, focusing on practical considerations. We discuss features of different immunodeficient recipient mouse strains, sources of human hematopoietic stem cells, advances in expansion and genetic modification of hematopoietic stem cells, and techniques to modulate the cytokine environment of recipient mice, in order to enhance reconstitution of specific human blood lineage cells. We highlight the opportunities created by new technologies and discuss practical considerations on how to make best use of the widening array of basic models for specific research applications.

Enhanced homing of mesenchymal stem cells for in situ niche remodeling and bone regeneration

Mesenchymal stem cells(MSCs)transplantation is a promising strategy for osteoporosis treatment.However,limited sources and poor tissue-homing efficiency limit their clinical capabilities.In this study,we isolated a kind of MSCs from women’s menstrual blood(MenSCs)noninvasively and established a novel MSCs bone marrow-targeted delivery system by utilizing waterin-oil-in-water droplet microfluidics.MenSCs were encapsulated withinβ-cyclodextrin-functionalized alginate microcapsules loaded with zoledronates,which has a high affinity for bone.With this delivery system,MenSCs could be preferentially delivered to the bone marrow tissues via intravenous infusion,and restored bone mass by remodeling the bone marrow niche in situ in ovariectomized mouse models.Moreover,scRNA-seq analysis demonstrated that those MenSCs homed to the bone marrow recruited CD4^(+)FOXP3^(+)natural regulatory T(nT_(reg))cells by secreting CCL28.The recruited nTreg promoted CD8^(+)T cells to secret Wnt family member 10B(WNT10B),activating the Wnt signaling in osteoblasts and thus promoting bone formation in situ in the bone marrow.This study reveals a promising application of MenSCs in postmenopausal osteoporosis treatment and highlights the clinical value of MenSCs by encouraging women to reserve autologous MenSCs before menopause to prevent and alleviate postmenopausal osteoporosis.

Interleukin-7 Receptor Signaling Network:An Integrated Systems Perspective

Interleukin-7 （IL-7） is an essential cytokine for the development and homeostatic maintenance of T and B lymphocytes. Binding of IL-7 to its cognate receptor, the IL-7 receptor （IL-7R）, activates multiple pathways that regulate lymphocyte survival, glucose uptake, proliferation and differentiation. There has been much interest in understanding how IL-7 receptor signaling is modulated at multiple interconnected network levels. This review examines how the strength of the signal through the IL-7 receptor is modulated in T and B cells, including the use of shared receptor components, signaling crosstalk, shared interaction domains, feedback loops, integrated gene regulation, multimerization and ligand competition. We discuss how these network control mechanisms could integrate to govern the properties of IL-7R signaling in lymphocytes in health and disease. Analysis of IL-7 receptor signaling at a network level in a systematic manner will allow for a comprehensive approach to understanding the impact of multiple signaling pathways on lymphocyte biology. Cellular ＆ Molecular Immunology.

Exon-centric regulation of pyruvate kinase M alternative splicing via mutually exclusive exons

Alternative splicing of the pyruvate kinase M gene(PK-M)can generate the M2 isoform and promote aerobic glycolysis and tumor growth.However,the cancer-specific alternative splicing regulation of PK-M is not completely understood.Here,we demonstrate that PK-M is regulated by reciprocal effects on the mutually exclusive exons 9 and 10,such that exon 9 is repressed and exon 10 is activated in cancer cells.Strikingly,exonic,rather than intronic,cis-elements are key determinants of PK-M splicing isoform ratios.Using a systematic sub-exonic duplication approach,we identify a potent exonic splicing enhancer in exon 10,which differs from its homologous counterpart in exon 9 by only two nucleotides.We identify SRSF3 as one of the cognate factors,and show that this serine/arginine-rich protein activates exon 10 and mediates changes in glucose metabolism.These findings provide mechanistic insights into the complex regulation of alternative splicing of a key regulator of the Warburg effect,and also have implications for other genes with a similar pattern of alternative splicing.

Persistence of tumor-infiltrating CD8 T cells is tumor-dependent but antigen-independent

How tumor-infiltrating lymphocytes(TILs)that are tumor-specific but functionally tolerant persist in the antigen-expressing tumor tissue is largely unknown.We have previously developed a modified TRansgenic Adenocarcinoma of the Mouse Prostate(TRAMP)model where prostate cancer cells express the T-cell epitope SIYRYYGL(SIY)recognized by CD8 T cells expressing the 2C T-cell receptor(TCR)(referred to as TRP-SIY mice).In TRP-SIY mice,activated 2C T cells rapidly become tolerant following infiltration into the prostate tumor.In this study,we show that tolerant 2C T cells persist in the prostate tumor of TRP-SIY mice by proliferating slowly in a tumor-dependent,but antigen-,interleukin(IL)-7-and IL-15-independent manner.We also show that disappearance of 2C T cells from the lymphoid organs of TRP-SIY mice are due to antigen-induced T-cell contraction rather than altered trafficking or generalized T-cell depletion in the mice.Finally,we show that clonal T cells unreactive to SIY are equally capable of persisting in the prostate tumor.These findings suggest that while functional tolerance of TILs is induced by antigen,persistence of tolerant TILs in the tumor tissue is mediated by a novel mechanism:slow proliferation independent of antigen and homeostatic cytokines.These results also allow CD8 T-cell survival in the tumor environment to be compared with T-cell survival in chronic infection.

Of mice and men： what rodent models don＇t tell us

Work recently published in PNAS by The Inflammation and Host Response to Injury, Large Scale Collaborative Research Program1 compared the transcriptional responses in peripheral blood to inflammatory injuries （burns, blunt force trauma） and to endotoxin in human patients and in corresponding mouse models.

Immunity:研究开发出最优的HIV疫苗递送模式

HIV已不再占据头条新闻。这主要是因为抗逆转录病毒药物的成功开发已将HIV病毒感染导致的艾滋病（AIDS）转化为一种慢性的可控制的疾病。然而。当前在全世界大约0．367亿名HIV感染者中，仅约一半的人能够获得控制这种病毒所需的药物。与此同时。新的HIV感染率持续保持在非常高的水平，这突出强调了需要开发一种预防性疫苗。然而，几十年来。