Development Of Tumor Vaccines Research Articles

GelMA microneedle-loaded bio-derived nanovaccine shows therapeutic potential for gliomas

ABSTRACT Glioma is the most common primary malignant tumor of the central nervous system in adults. Although immunotherapy, especially tumor vaccines, has made some progress in the treatment of gliomas compared with surgery and radiotherapy. However, the lack of specific or relevant tumor antigens severely limits the further development of tumor vaccines. Here, we report a bio-derived vaccine (TMV@CpG) derived from glioma cell membrane vesicles and carrying TLR9 agonist CpG as adjuvant, which was loaded onto the GelMA microneedle to obtain the microneedle vaccine (MN-TMV@CpG). Microneedle vaccine fully utilize the innate immune cells rich in the skin, inducing stronger cellular immune responses. In subcutaneous tumor models, MN-TMV@CpG reversed the immune-suppressing microenvironment of tumor, and effectively inhibited tumor progression. In an intracranial tumor model, MN-TMV@CpG significantly prolonged the survival duration and induced stronger immune memory responses in tumor bearing mice when combined with anti-PD1 mAb. These results suggest that bio-derived nanovaccines can be used as a potential antitumor immunotherapy strategy.

Tumor Immunology Unveiled: Advances, Challenges, and Future Prospects in Cancer Immunotherapy

Among the most important disciplines in the field of immunology, tumor immunology holds a significant place due to its focus on the interaction between tumors and the immune system. With the advancement of immunotherapy technologies in recent years, tumor immunology has emerged as one of the most exciting areas in cancer research. In this article, we will examine in detail the research progress in tumor immunology, including the mechanisms by which tumor cells evade the immune system, the application of immune checkpoint inhibitors, the development of tumor vaccines and their application in clinical practice, and how the tumor microenvironment impacts immunotherapy.

Developments and applications of therapeutic tumor vaccines

The incidence and mortality rates of malignant tumors have rapidly increased. Cancer has become the leading cause of death worldwide. Traditional treatment methods such as surgery, chemotherapy, and radiation have limited effectiveness, with poor prognosis, drug resistance, and low specificity. As a result, cancer immunotherapy has emerged as a promising approach in biotechnology. The development and application of tumor vaccines in tumor immunotherapy have garnered significant attention. These vaccines employ TAA or TSA to activate the bodys specific immune response against tumor cells. This review provides an overview of the tumor microenvironment, tumor immunotherapy, and various types of therapeutic cancer vaccines, including peptide, cell, DC, nucleic acid (DNA and mRNA), and neoantigen vaccines. In conclusion, this review summarizes the current progress and future prospects of tumor vaccines.

Tumor-Associated Myeloid Cells Selective Delivery of a Therapeutic Tumor Nano-Vaccine for Overcoming Immune Barriers for Effective and Long-Term Cancer Immunotherapy.

Therapeutic cancer vaccines have the potential to induce regression of established tumors, eradicate microscopic residual lesions, and prevent metastasis and recurrence, but their efficacy is limited by the low antigenicity of soluble antigens and the immunosuppressive tumor-associated macrophages (TAMs) that promote tumor growth. In this study, a novel strategy is reported for overcoming these defenses: a dual-targeting nano-vaccine (NV) based on hepatitis B core antigen (HBcAg) derived virus-like particles (VLPs), N-M2T-gp100 HBc NV, equipped with both SIGNR+ dendritic cells (DCs)/TAMs-targeting ability and high-density display of tumor-associated antigen (TAA). N-M2T-gp100 HBc NVs-based immunotherapy has demonstrated an optimal interaction between tumor-associated antigens (TAAs) and the immune composition of the tumor microenvironment. In a melanoma model, N-M2T-gp100 HBc VLPs significantly reducing in situ and abscopal tumor growth, and provide long-term immune protection. This remarkable anti-tumor effect is achieved by efficiently boosting of T cells and repolarizing of M2-like TAMs. This work opens exciting avenues for the development of personalized tumor vaccines targeting not just melanoma but potentially a broad range of cancer types based on functionalized VLPs.

Identification of immune-related tumor antigens and immune subtypes in osteosarcoma

PurposeThe development of tumor vaccines has become a hot topic in immunotherapy for osteosarcoma (OS); however, more tumor antigens with stronger immunogenicity need to be identified. MethodsWe downloaded six sets of gene expression profile data from online databases. The overexpressed genes were analyzed, intersected, and used to calculate the immune infiltration abundance in the TARGET OS dataset based on their expression matrix. Potential tumor antigen genes were identified based on whether they exhibited a high correlation with the antigen-presenting cells (APCs). A total of 1330 immune-related genes (IRGs) from the ImmPort website were retrieved based on their expression, and the Consensus Cluster method was used to obtain immune subtypes of the OS samples. Prognosis, immune microenvironment, and sensitivity to drugs were compared among the immune subtypes. ResultsIn total, 680 genes were overexpressed in at least two datasets, of which TREM2, TNFRSF12A, and THY1 were positively correlated with different APCs. Based on the expression matrix of 1330 IRGs in TARGET-OS, two immune subtypes, IS1 and IS2, were identified. The prognosis of the IS1 subtype was better than that of IS2, the expression of immune checkpoint (ICP)-related genes was higher in patients with the IS1 subtype, and immune cell infiltration and sensitivity to 16 drugs were generally higher in IS1 subtype patients. ConclusionWe identified three APC-correlated genes that can be considered to code for potential novel tumor antigens for OS vaccines. Two immune subtypes in patients with OS were identified to implement personalized treatments using mRNA vaccines.

TripHLApan: predicting HLA molecules binding peptides based on triple coding matrix and transfer learning.

Human leukocyte antigen (HLA) recognizes foreign threats and triggers immune responses by presenting peptides to T cells. Computationally modeling the binding patterns between peptide and HLA is very important for the development of tumor vaccines. However, it is still a big challenge to accurately predict HLA molecules binding peptides. In this paper, we develop a new model TripHLApan for predicting HLA molecules binding peptides by integrating triple coding matrix, BiGRU + Attention models, and transfer learning strategy. We have found the main interaction site regions between HLA molecules and peptides, as well as the correlation between HLA encoding and binding motifs. Based on the discovery, we make the preprocessing and coding closer to the natural biological process. Besides, due to the input being based on multiple types of features and the attention module focused on the BiGRU hidden layer, TripHLApan has learned more sequence level binding information. The application of transfer learning strategies ensures the accuracy of prediction results under special lengths (peptides in length 8) and model scalability with the data explosion. Compared with the current optimal models, TripHLApan exhibits strong predictive performance in various prediction environments with different positive and negative sample ratios. In addition, we validate the superiority and scalability of TripHLApan's predictive performance using additional latest data sets, ablation experiments and binding reconstitution ability in the samples of a melanoma patient. The results show that TripHLApan is a powerful tool for predicting the binding of HLA-I and HLA-II molecular peptides for the synthesis of tumor vaccines. TripHLApan is publicly available at https://github.com/CSUBioGroup/TripHLApan.git.

Trichostatin A-modified vaccine provides superior protection against ovarian cancer formation and development.

More attention has been paid to immunotherapy for ovarian cancer and the development of tumor vaccines. We developed a trichostatin A (TSA)-modified tumor vaccine with potent immunomodulating activities that can inhibit the growth of ovarian cancer in rats and stimulate immune cell response in vivo. TSA-treated Nutu-19 cells inactivated by X-ray radiation were used as a tumor vaccine in rat ovarian cancer models. Prophylactic and therapeutic experiments were performed with TSA-modified tumor vaccine in rats. Flow cytometry and ELISpot assays were conducted to assess immune response. Immune cell expression in the spleen and thymus were detected by immunohistochemical staining. GM-CSF, IL-7, IL-17, LIF, LIX, KC, MCP-1, MIP-2, M-CSF, IP-10/CXCL10, MIG/CXCL9, RANTES, IL-4, IFN-γ, and VEGF expressions were detected with Milliplex Map Magnetic Bead Panel immunoassay. TSA vaccination in therapeutic and prophylactic models could effectively stimulate innate immunity and boost the adaptive humoral and cell-mediated immune responses to inhibit the growth and tumorigenesis of ovarian cancer. This vaccine stimulated the thymus into reactivating status and enhanced infiltrating lymphocytes in tumor-bearing rats. The expression of key immunoregulatory factors were upregulated in the vaccine group. The intensities of infiltrating CD4+ and CD8+ T cells and NK cells were significantly increased in the vaccine group compared to the control group (P<0.05). This protection was mainly dependent on the IFN-γ pathway and, to a much lesser extent, by the IL-4 pathway. The tumor cells only irradiated by X-ray as the control group still showed a slight immune effect, indicating that irradiated cells may also cause certain immune antigen exposure, but the efficacy was not as significant as that of the TSA-modified tumor vaccine. Our study revealed the potential application of the TSA-modified tumor vaccine as a novel tumor vaccine against tumor refractoriness and growth. These findings offer a better understanding of the immunomodulatory effects of the vaccine against latent tumorigenesis and progression. This tumor vaccine therapy may increase antigen exposure, synergistically activate the immune system, and ultimately improve remission rates. A vaccine strategy designed to induce effective tumor immune response is being considered for cancer immunotherapy.

Chimeric RNAs reveal putative neoantigen peptides for developing tumor vaccines for breast cancer.

We present here a strategy to identify immunogenic neoantigen candidates from unique amino acid sequences at the junctions of fusion proteins which can serve as targets in the development of tumor vaccines for the treatment of breastcancer. We mined the sequence reads of breast tumor tissue that are usually discarded as discordant paired-end reads and discovered cancer specific fusion transcripts using tissue from cancer free controls as reference. Binding affinity predictions of novel peptide sequences crossing the fusion junction were analyzed by the MHC Class I binding predictor, MHCnuggets. CD8+ T cell responses against the 15 peptides were assessed through in vitro Enzyme Linked Immunospot (ELISpot). We uncovered 20 novel fusion transcripts from 75 breast tumors of 3 subtypes: TNBC, HER2+, and HR+. Of these, the NSFP1-LRRC37A2 fusion transcript was selected for further study. The 3833 bp chimeric RNA predicted by the consensus fusion junction sequence is consistent with a read-through transcription of the 5'-gene NSFP1-Pseudo gene NSFP1 (NSFtruncation at exon 12/13) followed by trans-splicing to connect withLRRC37A2 located immediately 3' through exon 1/2. A total of 15 different 8-mer neoantigen peptides discovered from the NSFP1 and LRRC37A2 truncations were predicted to bind to a total of 35 unique MHC class I alleles with a binding affinity of IC50<500nM.); 1 of which elicited a robust immune response. Our data provides a framework to identify immunogenic neoantigen candidates from fusion transcripts and suggests a potential vaccine strategy to target the immunogenic neopeptides in patients with tumors carrying the NSFP1-LRRC37A2 fusion.

Zinc-Organometallic Framework Vaccine Controlled-Release Zn2+ Regulates Tumor Extracellular Matrix Degradation Potentiate Efficacy of Immunotherapy.

Tumor extracellular matrix (ECM) not only forms a physical barrier for T cells infiltration, but also regulates multiple immunosuppressive pathways, which is an important reason for immunotherapy failure. The cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway plays a key role in activating CD8+ T cells, maintaining CD8+ T cells stemness and enhancing the antitumor effect. Herein, a zinc-organometallic framework vaccine (ZPM@OVA-CpG) prepared by self-assembly, which achieves site-directed release of Zn2+ in dendritic cell (DC) lysosomes and tumor microenvironment under acidic conditions, is reported. The vaccine actively targets DC, significantly enhances cGAS-STING signal, promotes DC maturation and antigen cross-presentation, and induces strong activation of CD8+ T cells. Meanwhile, the vaccine reaches the tumor site, releasing Zn2+ , significantly up-regulates the activity of matrix metalloproteinase-2, degrades various collagen components of tumor ECM, effectively alleviates immune suppression, and significantly enhances the tumor infiltration and killing of CD8+ T cells. ZPM@OVA-CpG vaccine not only solves the problem of low antigen delivery efficiency and weak CD8+ T cells activation ability, but also achieves the degradation of tumor ECM via the vaccine for the first time, providing a promising therapeutic platform for the development of efficient novel tumor vaccines.

Identification of Immune Subtypes and Candidate mRNA Vaccine Antigens in Small Cell Lung Cancer.

Immune checkpoint inhibitors (ICIs) have demonstrated promising outcomes in small cell lung cancer (SCLC), but not all patients benefit from it. Thus, developing precise treatments for SCLC is a particularly urgent need. In our study, we constructed a novel phenotype for SCLC based on immune signatures. We clustered patients with SCLC hierarchically in 3 publicly available datasets according to the immune signatures. ESTIMATE and CIBERSORT algorithm were used to evaluate the components of the tumor microenvironment. Moreover, we identified potential mRNA vaccine antigens for patients with SCLC, and qRT-PCR were performed to detect the gene expression. We identified 2 SCLC subtypes and named Immunity High (Immunity_H) and Immunity Low (Immunity_L). Meanwhile, we obtained generally consistent results by analyzing different datasets, suggesting that this classification was reliable. Immunity_H contained the higher number of immune cells and a better prognosis compared to Immunity_L. Gene-set enrichment analysis revealed that several immune-related pathways such as cytokine-cytokine receptor interaction, programmed cell death-Ligand 1 expression and programmed cell death-1 checkpoint pathway in cancer were hyperactivated in the Immunity_H. However, most of the pathways enriched in the Immunity_L were not associated with immunity. Furthermore, we identified 5 potential mRNA vaccine antigens of SCLC (NEK2, NOL4, RALYL, SH3GL2, and ZIC2), and they were expressed higher in Immunity_L, it indicated that Immunity_L maybe more suitable for tumor vaccine development. SCLC can be divided into Immunity_H and Immunity_L subtypes. Immunity_H may be more suitable for treatment with ICIs. NEK2, NOL4, RALYL, SH3GL2, and ZIC2 may be act as potential antigens for SCLC.

Crosstalk of ferroptosis regulators and tumor immunity in pancreatic adenocarcinoma: novel perspective to mRNA vaccines and personalized immunotherapy.

Pancreatic adenocarcinoma (PAAD) is the eighth leading cause of cancer-related mortality that causes serious physical and mental burden to human. Reactive oxygen species accumulation and iron overload might enable ferroptosis-mediated cancer therapies. This study was to elusive novel ferroptosis regulator and its association with immune microenvironment and PD-L1 in PAAD. RNA-seq data and relevant information were obtained from The Cancer Genome Atlas and Genotype-Tissue Expression. The R packages "ggplot2" and "pheatmap" were used to the expression of 20 ferroptosis regulators between PAAD and normal tissues. The R package "ConsensusClusterPlus", "survival", "survminer", "immunedeconv", and TIDE algorithm performed consensus clustering, overall survival, progression-free survival, disease free survival, immune infiltration level, and immunotherapy responses between cluster 1 and cluster 2. The prognostic value was confirmed by the Kaplan-Meier curves, receiver operating characteristic curve, univariate and multivariate cox regression, and nomogram. Moreover, the relationship of FANCD2 and immunity, drug sensitivity was investigated by R package "ggstatsplot", "immunedeconv", "ggalluvial" and "pRRophetic". Besides, the qRT-PCR, immunohistochemistry and western blotting detected the expression of FANCD2 in PAAD cell lines. Most ferroptosis regulators were up-regulated in PAAD, while the expression of LPCAT3, MT1G, and GLS2 was down-regulated in PAAD (P < 0.05), indicting there was a positively correlation among ferroptosis regulators. Based on clustering parameter, we identified cluster 1 and cluster 2, and cluster 2 had a better prognosis for patients with PAAD. The immune infiltration level of cluster 1 was higher in macrophage M1, myeloid dendritic cell, T cell CD4 + Th2, B cell, T cell CD8 + central memory, immune score, and microenvironment score than cluster 2 in PAAD. Moreover, FANCD2 was up-regulated in PAAD by public databases, immunohistochemistry, qRT-PCR and Western blotting, which had closely related to overall survival, immune microenvironment, and drug sensitivity. A novel crosstalk of ferroptosis exhibits a favourable prognostic performance and builds a robust theoretical foundation for mRNA vaccine and personalized immunotherapy. FANCD2 could be an effective for prognostic recognition, immune efficacy evaluation, and mRNA vaccine for patients with PAAD, providing a vital guidance for further study of regulating tumor immunity and vaccine development.

A promising self-nanoemulsifying adjuvant with plant-derived saponin D boosts immune response and exerts an anti-tumor effect.

The low immunogenicity of tumor antigens and unacceptable toxicity of adjuvants has hindered the application and development of tumor vaccines. Hence, we designed a novel anti-tumor vaccine composed of a plant-derived immunostimulant molecular nanoadjuvant (a self-nanoemulsifying system, SND) and the antigen OVA, to reinvigorate the immune response and inhibit tumor progression. In this study, this novel nanoadjuvant with Saponin D (SND) was designed and prepared by low-energy emulsification methods. Several important characteristics of the SND, including morphology, size, polymer dispersity index (PDI), zeta potential, and stability, were estimated, and the cytotoxicity of the SND was evaluated by MTT assay. Additionally, the immune response in terms of antibody titer levels and cellular immunity were evaluated in vivo after immunization with the vaccine, and the preventative and therapeutic effects of this novel vaccine against tumors were estimated. Finally, the antigen release profile was determined by IVIS imaging and by in vivo assay. This SND nanoadjuvant had good characteristics including the average particle size of 26.35 ± 0.225 nm, narrow distribution of 0.221 ± 1.76, and stability zeta potential of -12.9 ± 0.83 mV. And also, it had good stability (size, PDI, zeta potential, antigen stability) and low toxicity in vitro and in vivo, and delayed antigen release in vivo. The humoral immune response (IgG, IgG1, IgG2a, and IgG2b) and cellular immune level (cytokines of splenocytes including IFN-γ, IL-4, IL-1β andIL-17A) were both improved greatly after injected immunization at 0, 14, 28 days with the novel nanoadjuvant and antigen OVA. Importantly, this novel nanoadjuvant combined with OVA might lead to the induction of the prevent and treatment efficacy in the E.G7-OVA tumor-bearing mice. These results suggested that this novel nanoadjuvant encapsulated natural plant immunostimulant molecular OPD could be a good candidate of tumor vaccine adjuvant for reinvigorating the immune response and powerfully inhibiting tumor growth effect.

Asymmetric Assembly and Self-Adjuvanted Antigen Delivery Platform for Improved Antigen Uptake and Antitumor Effect

The development of effective tumor vaccines is an important direction in the field of cancer prevention/immunotherapy. Efficient antigen delivery is essential for inducing effective antitumor responses for tumor vaccines. Lumazine synthase (BLS) from Brucella spp. is a decameric protein with delivery and adjuvant properties, but its application in tumor vaccines is limited. Here, we developed an antigen delivery platform by combining a BLS asymmetric assembly and the Plug-and-Display system of SpyCatcher/SpyTag. An asymmetric assembly system consisting of BLSke and BLSdr was developed to equally assemble two molecules. Then, the MHC-I-restricted ovalbumin peptide (OVA(257-264) SIINFEKL) was conjugated with BLSke, and a cell-penetrating peptide (CPP) KALA was conjugated with BLSdr using the SpyCatcher/SpyTag system. KALA modification enhanced internalization of OVA peptides by DCs as well as promoted the maturation of DCs and the cross-presentation of SIINFEKL. Moreover, the immunotherapy of a KALA-modified vaccine suppressed tumor growth and enhanced CD8+ T cell responses in E.G7-OVA tumor-bearing mice. In the prophylactic model, KALA-modified vaccination showed the most significant protective effect and significantly prolonged the survival period of tumor challenged mice. In conclusion, the asymmetric assembly platform equally assembles two proteins or peptides, avoiding their spatial or functional interference. This asymmetric assembly and Plug-and-Display technology provide a universal platform for rapid development of personalized tumor vaccines.

Monocytes reprogrammed by tumor microparticle vaccine inhibit tumorigenesis and tumor development

Tumor microparticles (T-MPs) are considered as a tumor vaccine candidate. Although some studies have analyzed the mechanism of T-MPs as tumor vaccine, we still lack understanding of how T-MPs stimulate a strong anti-tumor immune response. Here, we show that T-MPs induce macrophages to release a key chemotactic factor CCL2, which attracts monocytes to the vaccine injection site and enhances endocytosis of antigen. Monocytes subsequently enter the draining lymph node, and differentiate into monocyte-derived DCs (moDCs), which present tumor antigens to T lymphocytes and deliver a potent anti-tumor immune response. Mechanically, T-MPs activate the cGAS-STING signaling through DNA fragments, and then induce monocytes to upregulate the expression of IRF4, which is a key factor for monocyte differentiation into moDCs. More importantly, monocytes that have endocytosed T-MPs acquire the ability to treat tumors. Collectively, this work might provide novel vaccination strategy for the development of tumor vaccines and facilitate the application of T-MPs for clinic oncotherapy.

Eliciting effective tumor immunity against ovarian cancer by cancer stem cell vaccination

Advanced ovarian cancer (OC) patients have limited benefit from current relevant cytotoxic and targeted therapies following debulking surgery. Therefore, new therapeutic strategies are in urgent need. Immunotherapy has shown great potential in tumor treatment, especially in tumor vaccine development. The study objective was to evaluate the immune effects of cancer stem cells (CSCs) vaccines on OC. The CD44+CD117+CSCs were isolated from human OC HO8910 and SKOV3 cells using the magnetic cell sorting system; the cancer stem-like cells were selected from murine OC ID8 cell by no-serum formed sphere culture. The CSC vaccines were prepared by freezing and thawing these CSCs, which were then injected into mice followed by challenging the different OC cells. The in vivo antitumor efficacy of CSC immunization revealed the vaccines were capable of significantly provoking immune responses to autologous tumor antigens in vaccinated mice as the mice were found to have markedly inhibited tumor growth, prolonged survival, and decreased CSC counts in OC tissues when compared to mice without the CSC vaccination. The in vitro cytotoxicities of immunocytes toward SKOV3, HO8910 and ID8 cells indicated a significant killing efficacy compared with the controls. However, the antitumor efficacy was remarkably reduced whilst the mucin-1 expression in CSC vaccines was down-regulated by small interfering RNA. Overall, findings from this study provided the evidence that has deepened our understanding of CSC vaccine immunogenicity and anti-OC efficacy, particularly for the role of dominant antigen mucin-1. It is possible to turn the CSC vaccine into an immunotherapeutic approach against ovarian cancer.

Antitumor effect of invasive Lactobacillus plantarum delivering associated antigen gene sHSP between Trichinella spiralis and Lewis lung cancer cells.

Cancer is a frequent disease that seriously harms human health, but there are no ideal therapies for it. Currently, some food-grade microorganisms such as Lactobacillus plantarum have shown better anti-tumor effects. Here, recombinant Lactobacillus plantarum lives vector vaccine NC8-sHSP was generated by using the invasive Lactobacillus plantarum NC8 expressing FnBPA to deliver the associated antigen gene sHSP between trichinella spiralis and Lewis lung cancer cells (LLC) to host cells. NC8-sHSP colonized the mouse intestine to deliver plasmids to intestinal epithelial cells and controlled the growth of LLC by inducing humoral, cellular, and mucosal immunity. The tumor inhibition rates were 62.36% and 68.37% in the prophylactic assay and 40.76% and 44.22% in the treatment assay, respectively. Recombination of Lactobacillus plantarum did not cause significant damage. In conclusion, the recombinant invasive Lactobacillus plantarum constructed in this study has better anti-Lewis lung cancer effects in mice, which will provide new ideas for the application of food-grade microorganisms in anti-tumor and the development of oral tumor vaccines.

Macro-microporous ZIF-8 MOF complexed with lysosomal pH-adjusting hexadecylsulfonylfluoride as tumor vaccine delivery systems for improving anti-tumor cellular immunity.

Tumor vaccine therapy, which can induce tumor antigen-specific cellular immune responses to directly kill tumor cells, is considered to be one of the most promising tumor immunotherapies. How to elicit effective tumor antigen-specific cellular immunity is the key for the development of tumor vaccines. However, current tumor vaccines with conventional antigen delivery systems mainly induce humoral immunity but not effective cellular immunity. In this study, based on pH-sensitive, ordered macro-microporous zeolitic imidazolate framework-8 (SOM-ZIF-8) and hexadecylsulfonylfluoride (HDSF), an intelligent tumor vaccine delivery system SOM-ZIF-8/HDSF was developed to elicit potent cellular immunity. Results demonstrated that the SOM-ZIF-8 particles could efficiently encapsulate antigen into the macropores, promote antigen uptake by antigen-presenting cells, facilitate lysosomal escape, and enhance antigen cross-presentation and cellular immunity. In addition, the introduction of HDSF could up-regulate the lysosomal pH to protect antigens from acid degradation, which further promoted antigen cross-presentation and cellular immunity. The immunization tests showed that the tumor vaccines based on the delivery system improved antigen-specific cellular immune response. Moreover, the tumor vaccines significantly inhibited tumor growth in B16 melanoma-bearing C57BL/6 mice. These results indicate that SOM-ZIF-8/HDSF as an intelligent vaccine delivery system could be used for the development of novel tumor vaccines.

Natural blood plasma-based hydrogels as tumor vaccines delivery systems to enhance biomimetic recruitment of antigen presenting cells for tumor immunotherapy.

Tumor vaccines can inhibit or eliminate tumors by vaccinating hosts with tumor antigens to activate antigen-specific immune responses and have gained wild attention. However, their clinical application efficacy is often comprised due to the low safety and poor efficiency of vaccine adjuvants/carriers. Specifically, the adjuvants/carriers usually could not efficiently recruit antigen presenting cells (APCs) to capture the vaccines or directly damage these cells. Therefore, ideal tumor vaccine adjuvants/carriers should effectively recruit APCs and be friendly to the cells for well keeping their bio-functions. In this work, injectable natural blood plasma hydrogel was used for the first time to encapsulate tumor antigens and adjuvant (Mn2+) for the construction of a personalized tumor vaccine. This kind of natural hydrogel with extremely high bio-safety has great potential to friendly recruit APCs in a biomimetic manner by simulating the natural degradation process of subcutaneous blood stasis. The obtained results show that the natural blood plasma hydrogel-based tumor vaccines could significantly promote the recruitment of APCs, well maintain the immuno-functions of the cells, and finally induce efficient anti-tumor immune responses. Compared with traditional tumor vaccines, this natural blood plasma-based hydrogel provides a new strategy for the development of safe and effective tumor vaccines.

Tumor Microenvironment-Activated Hydrogel Platform with Programmed Release Property Evokes a Cascade-Amplified Immune Response against Tumor Growth, Metastasis and Recurrence.

In situ tumor vaccines (ITV) have been recognized as a promising antitumor strategy since they contain the entire tumor-specific antigens, avoiding tumor cells from evading immune surveillance due to antigen loss. However, the therapeutic benefits of ITV are limited by obstacles such as insufficient antigen loading, inadequate immune system activation, and immunosuppressive tumor microenvironments (TME). Herein, a tumor microenvironment-activated hydrogel platform (TED-Gel) with programmed drug release property is constructed for cascaded amplification of the anti-tumor immune response elicited by ITV. Both doxorubicin (Dox) and cytosine-phosphate-guanosine oligodeoxynucleotides (CpG) are released first, in which Dox induces immunogenic tumor cell death causing additional tumor antigen release and leading the dying primary tumor cells into autologous tumor vaccine, and the released CpG promotes antigen presenting cell activation. Subsequently, the decomposed scaffold materials in conjunction with CpG, turn the anti-inflammatory M2-like macrophages into the M1 type, reversing the immunosuppressive TME. With decomposition of the TED-Gel, large amounts of macromolecule anti-PD-L1 antibodies are liberated, reinvigorating the exhausted effector T cells. In vivo studies demonstrate that TED-Gel significantly inhibits the primary, distant and rechallenged tumor growth. Overall, the simple and powerful TED-Gel provides an alternative strategy for the future development of tumor vaccines with broad application.

Identification of tumor antigens and immune subtypes in breast cancer for mRNA vaccine development.

BackgroundPoor prognosis, resistance to chemotherapy, insensitivity to radiotherapy, and a high prevalence of adverse drug reactions remain urgent issues for breast cancer (BC) patients. Increased knowledge of tumor immunobiology and vaccine development suggests the possibility of cancer vaccination. Here, we investigated potential BC-associated antigens for the development of an anti-BC mRNA vaccine and populations suitable for mRNA vaccination.MethodsGene expression and clinical data were obtained from The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC). The single-cell sequencing data were obtained from the Single Cell Portal platform. cBioPortal was used to visualize and compare genetic alterations. Correlations between immune cell infiltration and antigen expression were visualized with the Tumor Immune Estimation Resource (TIMER). Immune subtypes were identified by consensus clustering and analysis of immune infiltration. Biomarkers for the assessment of mRNA vaccination suitability were investigated.ResultsThree tumor-associated antigens, CD74, IRF1, and PSME2, that showed overexpression, amplification, and mutation and were linked with prognosis and immune cell infiltration, were identified. Single-cell sequencing analysis showed the expression of the three tumor-associated antigens in different cells of BC. Three immune subtypes were identified among BC patients, with Cluster B patients having a tumor microenvironment conducive to immunotherapy. These subtypes also showed different expression patterns of immune checkpoints, immune cell death-promoting genes, and response to immune checkpoint inhibitor (ICI) therapy. Thus, we identified five biomarkers that could be applied for assessing vaccination suitability and predicted drugs that would be appropriate for patients unsuited for vaccination.ConclusionsOur findings suggest new directions for the development of mRNA vaccines against breast cancer.