The immune system plays key roles in tissue homeostatic and disease processes, and manipulation of innate and adaptive immune responses is of great promise for a wide array of human afflictions, ...including tissue repair and regeneration, cancer, autoimmune syndromes and chronic infections. Systemic approaches to immunomodulation can correct both hypoactive and hyperactive immunity; however, they typically interfere with the homeostatic role of the immune system at nontarget sites, are associated with lifelong comorbidities and potentially fatal side effects. To overcome these issues, macroscale delivery devices can be placed at sites of interest in the body and engineered to locally control the pharmacokinetics of immunomodulatory agents, including small molecules, macromolecules and cells. In this Review, we outline important cellular targets of immunotherapies in tissue repair and cancer and discuss how macroscale delivery devices can be designed to modulate the release of molecular factors to impact immune cell behaviour, control the fate of delivered therapeutic cells or directly recruit, house and modulate host cells for immunotherapy applications.Macroscale delivery devices can be used to manipulate innate and adaptive immune responses. In this Review, the authors highlight important cellular targets of immunotherapies in tissue repair and cancer and discuss macroscale biomaterials strategies for therapeutic immunomodulation.
Existing strategies to enhance peptide immunogenicity for cancer vaccination generally require direct peptide alteration, which, beyond practical issues, may impact peptide presentation and result in ...vaccine variability. Here, we report a simple adsorption approach using polyethyleneimine (PEI) in a mesoporous silica microrod (MSR) vaccine to enhance antigen immunogenicity. The MSR-PEI vaccine significantly enhanced host dendritic cell activation and T-cell response over the existing MSR vaccine and bolus vaccine formulations. Impressively, a single injection of the MSR-PEI vaccine using an E7 peptide completely eradicated large, established TC-1 tumours in about 80% of mice and generated immunological memory. When immunized with a pool of B16F10 or CT26 neoantigens, the MSR-PEI vaccine eradicated established lung metastases, controlled tumour growth and synergized with anti-CTLA4 therapy. Our findings from three independent tumour models suggest that the MSR-PEI vaccine approach may serve as a facile and powerful multi-antigen platform to enable robust personalized cancer vaccination.
Most cancer vaccines target peptide antigens, necessitating personalization owing to the vast inter-individual diversity in major histocompatibility complex (MHC) molecules that present peptides to T ...cells. Furthermore, tumours frequently escape T cell-mediated immunity through mechanisms that interfere with peptide presentation
. Here we report a cancer vaccine that induces a coordinated attack by diverse T cell and natural killer (NK) cell populations. The vaccine targets the MICA and MICB (MICA/B) stress proteins expressed by many human cancers as a result of DNA damage
. MICA/B serve as ligands for the activating NKG2D receptor on T cells and NK cells, but tumours evade immune recognition by proteolytic MICA/B cleavage
. Vaccine-induced antibodies increase the density of MICA/B proteins on the surface of tumour cells by inhibiting proteolytic shedding, enhance presentation of tumour antigens by dendritic cells to T cells and augment the cytotoxic function of NK cells. Notably, this vaccine maintains efficacy against MHC class I-deficient tumours resistant to cytotoxic T cells through the coordinated action of NK cells and CD4
T cells. The vaccine is also efficacious in a clinically important setting: immunization following surgical removal of primary, highly metastatic tumours inhibits the later outgrowth of metastases. This vaccine design enables protective immunity even against tumours with common escape mutations.
Targeted immunomodulation of dendritic cells (DCs) in vivo will enable manipulation of T-cell priming and amplification of anticancer immune responses, but a general strategy has been lacking. Here ...we show that DCs concentrated by a biomaterial can be metabolically labelled with azido groups in situ, which allows for their subsequent tracking and targeted modulation over time. Azido-labelled DCs were detected in lymph nodes for weeks, and could covalently capture dibenzocyclooctyne (DBCO)-bearing antigens and adjuvants via efficient Click chemistry for improved antigen-specific CD8
T-cell responses and antitumour efficacy. We also show that azido labelling of DCs allowed for in vitro and in vivo conjugation of DBCO-modified cytokines, including DBCO-IL-15/IL-15Rα, to improve priming of antigen-specific CD8
T cells. This DC labelling and targeted modulation technology provides an unprecedented strategy for manipulating DCs and regulating DC-T-cell interactions in vivo.
Although adoptive T cell therapy provides the T cell pool needed for immediate tumor debulking, the infused T cells generally have a narrow repertoire for antigen recognition and limited ability for ...long-term protection. Here, we present a hydrogel that locally delivers adoptively transferred T cells to the tumor site while recruiting and activating host antigen-presenting cells with GMCSF or FLT3L and CpG, respectively. T cells alone loaded into these localized cell depots provided significantly better control of subcutaneous B16-F10 tumors than T cells delivered through direct peritumoral injection or intravenous infusion. T cell delivery combined with biomaterial-driven accumulation and activation of host immune cells prolonged the activation of the delivered T cells, minimized host T cell exhaustion, and enabled long-term tumor control. These findings highlight how this integrated approach provide both immediate tumor debulking and long-term protection against solid tumors, including against tumor antigen escape.
Mechanical stimulation (mechanotherapy) can promote skeletal muscle repair, but a lack of reproducible protocols and mechanistic understanding of the relation between mechanical cues and tissue ...regeneration limit progress in this field. To address these gaps, we developed a robotic device equipped with real-time force control and compatible with ultrasound imaging for tissue strain analysis. We investigated the hypothesis that specific mechanical loading improves tissue repair by modulating inflammatory responses that regulate skeletal muscle regeneration. We report that cyclic compressive loading within a specific range of forces substantially improves functional recovery of severely injured muscle in mice. This improvement is attributable in part to rapid clearance of neutrophil populations and neutrophil-mediated factors, which otherwise may impede myogenesis. Insights from this work will help advance therapeutic strategies for tissue regeneration broadly.
Vaccines have shown significant promise in eliciting protective and therapeutic responses. However, most effective vaccines require several booster shots, and it is challenging to generate responses ...against synthetic molecules and peptides often used to increase target specificity and improve vaccine stability. As continuous antigen uptake and processing by antigen‐presenting cells and persistent toll‐like receptor priming can amplify humoral immunity, it is explored whether a single injection of a mesoporous silica micro‐rod (MSR) vaccine containing synthetic molecules and peptides can generate potent and durable humoral immunity. A single injection of the vaccine targeting a gonadotropin‐releasing hormone (GnRH) decapeptide elicits high anti‐GnRH titer for over 12 months and generated higher titers than bolus or alum formulations. Targeting a Her2/neu peptide within the Trastuzumab binding domain causes immunoreactivity to Her2 on tumor cells and, MSR vaccines against nicotine generated long‐term anti‐nicotine antibodies. A single MSR injection induced germinal center (GC) activity for more than 3 weeks, generated memory B cells, and 7 days of immunostimulation by the vaccine is required to generate effective antibody responses. The MSR vaccine represents a promising technology to bypass the need for multiple immunizations and enhance long‐term antibody production in the context of reproductive biology, cancer, and chronic addiction.
Mesoporous silica rods (MSRs) are used as an injectable vaccination platform to induce antibody against peptides and other small antigens. MSRs form subcutaneous scaffolds, recruit and activate antigen‐presenting cells, and deliver the antigen for prolonged periods of time. Compared to conventional immunizations, MSR vaccines increase the generation of memory B‐cells with a single injection.
Short peptides are the minimal modality of antigen recognized by cellular immunity and are therefore considered a safe and highly specific source of antigen for vaccination. Nevertheless, successful ...peptide immunotherapy is limited by the short half-life of peptide antigens in vivo as well as their weak immunogenicity. We recently reported a vaccine strategy based on dendritic cell-recruiting Mesoporous Silica Rod (MSR) scaffolds to enhance T-cell responses against subunit antigen. In this study, we investigated the effect of covalently conjugating peptide antigens to MSRs to increase their retention in the scaffolds. Using both stable thioether and reducible disulfide linkages, peptide conjugation greatly increased peptide loading compared to passive adsorption. In vitro, Bone Marrow derived Dendritic Cells (BMDCs) could present Ovalbumin (OVA)-derived peptides conjugated to MSRs and induce antigen-specific T-cell proliferation. Stable conjugation decreased presentation in vitro while reducible conjugation maintained levels of presentation as high as soluble peptide. Compared to soluble peptide, in vitro, expansion of OT-II T-cells was not affected by adsorption or stable conjugation to MSRs but was enhanced with reversible conjugation to MSRs. Both conjugation schemes increased peptide residence time in MSR scaffolds in vivo compared to standard bolus injections or a simple adsorption method. When MSR scaffolds loaded with GM-CSF and CpG-ODN were injected subcutaneously, recruited dendritic cells could present antigen in situ with the stable conjugation increasing presentation capacity. Overall, this simple conjugation approach could serve as a versatile platform to efficiently incorporate peptide antigens in MSR vaccines and potentiate cellular responses.
Traditional bolus vaccines often fail to sustain robust adaptive immune responses, typically requiring multiple booster shots for optimal efficacy. Additionally, these provide few opportunities to ...control the resulting subclasses of antibodies produced, which can mediate effector functions relevant to distinct disease settings. Here, it is found that three scaffold‐based vaccines, fabricated from poly(lactide‐co‐glycolide) (PLG), mesoporous silica rods, and alginate cryogels, induce robust, long‐term antibody responses to a model peptide antigen gonadotropin‐releasing hormone with single‐shot immunization. Compared to a bolus vaccine, PLG vaccines prolong germinal center formation and T follicular helper cell responses. Altering the presentation and release of the adjuvant (cytosine‐guanosine oligodeoxynucleotide, CpG) tunes the resulting IgG subclasses. Further, PLG vaccines elicit strong humoral responses against disease‐associated antigens HER2 peptide and pathogenic E. coli, protecting mice against E. coli challenge more effectively than a bolus vaccine. Scaffold‐based vaccines may thus enable potent, durable and versatile humoral immune responses against disease.
It is demonstrated that scaffold‐based vaccines elicit robust and durable antibody responses after single‐shot vaccination, against target antigens involved in reproduction, cancer, and infectious disease. Modifying the presentation and release of adjuvant from the scaffold affects the quality and antibody subclass of the resulting immune response, which may be tailored to these distinct applications.
Disruption of the tumor extracellular matrix (ECM) may alter immune cell infiltration into the tumor and antitumor T cell priming in the tumor-draining lymph nodes (tdLNs). Here, we explore how ...intratumoral enzyme treatment (ET) of B16 melanoma tumors with ECM-depleting enzyme hyaluronidase alters adaptive and innate immune populations, including T cells, DCs, and macrophages, in the tumors and tdLNs. ET increased CD103
+
DC abundance in the tdLNs, as well as antigen presentation of a model tumor antigen ovalbumin (OVA), eliciting local OVA-specific CD8
+
T cell responses. Delivered in combination with a distant cryogel-based cancer vaccine, ET increased the systemic antigen-specific CD8
+
T cell response. By enhancing activity within the tdLN, ET may broadly support immunotherapies in generating tumor-specific immunity.
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