EISA in Tandem with ICD to Form In Situ Nanofiber Vaccine for Enhanced Tumor Radioimmunotherapy

Radiotherapy (RT) can produce a vaccine effect and remodel a tumor microenvironment (TME) by inducing immunogenic cell death (ICD) and inflammation in tumors. However, RT alone is insufficient to elicit a systemic antitumor immune response owing to limited antigen presentation, immunosuppressive microenvironment, and chronic inflammation within the tumor. Here, we report a novel strategy for the generation of in situ peptide-based nanovaccines via enzyme-induced self-assembly (EISA) in tandem with ICD. As ICD progresses, the peptide Fbp-pY, dephosphorylated by alkaline phosphatase (ALP), forms a fibrous nanostructure around the tumor cells, resulting in the capture and encapsulation of the autologous antigens produced by radiation. Utilizing the adjuvant and controlled-release advantages of self-assembling peptides, this nanofiber vaccine effectively increased antigen accumulation in the lymph nodes and cross-presentation by antigen-presenting cells. In addition, the inhibition of COX-2 expression by the nanofibers promoted the repolarization of M2-macrophages into M1 and reduced the number of Tregs and MDSCs required for TME remodeling. As a result, the combination of nanovaccines and RT significantly enhanced the therapeutic effect on 4T1 tumors compared with RT alone, suggesting a promising treatment strategy for tumor radioimmunotherapy. This article is protected by copyright. All rights reserved.

[1]  Cuihong Yang,et al.  Tumor‐Specific Peroxynitrite Overproduction Disrupts Metabolic Homeostasis for Sensitizing Melanoma Immunotherapy , 2023, Advanced materials.

[2]  Dunwan Zhu,et al.  Vaccine-like nanomedicine for cancer immunotherapy. , 2023, Journal of controlled release : official journal of the Controlled Release Society.

[3]  Ling Wang,et al.  Enzyme-Instructed Peptide Assembly Favored by Preorganization for Cancer Cell Membrane Engineering. , 2023, Journal of the American Chemical Society.

[4]  Xiaodong Zhang,et al.  In situ generation of micrometer-sized tumor cell-derived vesicles as autologous cancer vaccines for boosting systemic immune responses , 2022, Nature Communications.

[5]  Fu‐Gen Wu,et al.  Intracellular Enzyme-Instructed Self-Assembly of Peptides (IEISAP) for Biomedical Applications , 2022, Molecules.

[6]  F. Ginhoux,et al.  Systemic vaccination induces CD8+ T cells and remodels the tumor microenvironment , 2022, Cell.

[7]  P. Allavena,et al.  Macrophages as tools and targets in cancer therapy , 2022, Nature Reviews Drug Discovery.

[8]  Weiwei Zeng,et al.  Polypyrrole Nanoenzymes as Tumor Microenvironment Modulators to Reprogram Macrophage and Potentiate Immunotherapy , 2022, Advanced science.

[9]  A. Rodal,et al.  Enzyme-Responsive Peptide Thioesters for Targeting Golgi Apparatus. , 2022, Journal of the American Chemical Society.

[10]  J. Lovell,et al.  Irradiation conditioning of adjuvanted, autologous cancer cell membrane nanoparticle vaccines , 2021, Chemical Engineering Journal.

[11]  Chujun Li,et al.  Next frontier in tumor immunotherapy: macrophage-mediated immune evasion , 2021, Biomarker research.

[12]  C. Bieberich,et al.  Reactivation of the tumor suppressor PTEN by mRNA nanoparticles enhances antitumor immunity in preclinical models , 2021, Science Translational Medicine.

[13]  Dunwan Zhu,et al.  Symphony of nanomaterials and immunotherapy based on the cancer–immunity cycle , 2021, Acta pharmaceutica Sinica. B.

[14]  L. Qiu,et al.  Enzyme-mediated in situ self-assembly promotes in vivo bioorthogonal reaction for pretargeted multimodality imaging. , 2021, Angewandte Chemie.

[15]  Jun Xu,et al.  ATP‐Responsive Smart Hydrogel Releasing Immune Adjuvant Synchronized with Repeated Chemotherapy or Radiotherapy to Boost Antitumor Immunity , 2021, Advanced materials.

[16]  C. Hammer,et al.  Antigen presentation in cancer: insights into tumour immunogenicity and immune evasion , 2021, Nature Reviews Cancer.

[17]  J. Lysaght,et al.  Radiotherapy, immunotherapy, and the tumour microenvironment: Turning an immunosuppressive milieu into a therapeutic opportunity. , 2021, Cancer letters.

[18]  G. Colombo,et al.  Prostaglandin E2 and Cancer: Insight into Tumor Progression and Immunity , 2020, Biology.

[19]  Baoquan Ding,et al.  A DNA nanodevice-based vaccine for cancer immunotherapy , 2020, Nature Materials.

[20]  Bing Xu,et al.  Enzymatic Noncovalent Synthesis. , 2020, Chemical reviews.

[21]  J. Zou,et al.  Burst release of encapsulated annexin A5 in tumours boosts cytotoxic T-cell responses by blocking the phagocytosis of apoptotic cells , 2020, Nature Biomedical Engineering.

[22]  Wanzun Lin,et al.  Radiation-induced small extracellular vesicles as “carriages” promote tumor antigen release and trigger antitumor immunity , 2020, Theranostics.

[23]  Gang Wu,et al.  Irradiated tumor cell–derived microparticles mediate tumor eradication via cell killing and immune reprogramming , 2020, Science Advances.

[24]  KyungMann Kim,et al.  Development of an In Situ Cancer Vaccine via Combinational Radiation and Bacterial‐Membrane‐Coated Nanoparticles , 2019, Advanced materials.

[25]  I. Melero,et al.  Dendritic cells in cancer immunology and immunotherapy , 2019, Nature Reviews Immunology.

[26]  J. Schneider,et al.  De novo design of selective membrane-active peptides via enzymatic control of their conformational bias on the cell surface. , 2019, Angewandte Chemie.

[27]  L. Galluzzi,et al.  Macrophages and Metabolism in the Tumor Microenvironment. , 2019, Cell metabolism.

[28]  Xiaodan Chen,et al.  Sustained Release of Two Bioactive Factors from Supramolecular Hydrogel Promotes Periodontal Bone Regeneration. , 2019, ACS nano.

[29]  Zhimou Yang,et al.  Enzyme‐Instructed Self‐Assembly (EISA) and Hydrogelation of Peptides , 2019, Advanced materials.

[30]  Bing Xu,et al.  Instructed Assembly as Context-Dependent Signaling for the Death and Morphogenesis of Cells. , 2019, Angewandte Chemie.

[31]  Hannah Carter,et al.  Evolutionary Pressure against MHC Class II Binding Cancer Mutations , 2018, Cell.

[32]  Luofu Wang,et al.  The roles of the COX2/PGE2/EP axis in therapeutic resistance , 2018, Cancer and Metastasis Reviews.

[33]  J. Hesser,et al.  Using immunotherapy to boost the abscopal effect , 2018, Nature Reviews Cancer.

[34]  Tian Zhang,et al.  Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy , 2017, Nature Nanotechnology.

[35]  Alberto Mantovani,et al.  Tumour-associated macrophages as treatment targets in oncology , 2017, Nature Reviews Clinical Oncology.

[36]  Joe Y. Chang,et al.  Immunotherapy and stereotactic ablative radiotherapy (ISABR): a curative approach? , 2016, Nature Reviews Clinical Oncology.

[37]  Changyang Gong,et al.  Enzyme‐Catalyzed Formation of Supramolecular Hydrogels as Promising Vaccine Adjuvants , 2016 .

[38]  Erik Sahai,et al.  Cyclooxygenase-Dependent Tumor Growth through Evasion of Immunity , 2015, Cell.

[39]  Kevin J. Harrington,et al.  The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence , 2015, Nature Reviews Cancer.

[40]  H. Ishwaran,et al.  Radiation and Dual Checkpoint Blockade Activates Non-Redundant Immune Mechanisms in Cancer , 2015, Nature.

[41]  Wei Zhang,et al.  A peptide-based nanofibrous hydrogel as a promising DNA nanovector for optimizing the efficacy of HIV vaccine. , 2014, Nano letters.

[42]  Bing Xu,et al.  D-amino acids boost the selectivity and confer supramolecular hydrogels of a nonsteroidal anti-inflammatory drug (NSAID). , 2013, Journal of the American Chemical Society.

[43]  S. Demaria,et al.  Radiation therapy to convert the tumor into an in situ vaccine. , 2012, International journal of radiation oncology, biology, physics.

[44]  Jun Yu,et al.  Cyclooxygenase-2 in tumorigenesis of gastrointestinal cancers: an update on the molecular mechanisms. , 2010, Cancer letters.

[45]  M. Hughes-Fulford,et al.  Arachidonic acid, an omega-6 fatty acid, induces cytoplasmic phospholipase A2 in prostate carcinoma cells. , 2005, Carcinogenesis.

[46]  Melody A. Swartz,et al.  Dendritic-cell trafficking to lymph nodes through lymphatic vessels , 2005, Nature Reviews Immunology.

[47]  N. Kawashima,et al.  Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. , 2004, International journal of radiation oncology, biology, physics.

[48]  W. Weichert,et al.  Elevated expression of cyclooxygenase‐2 is a negative prognostic factor for disease free survival and overall survival in patients with breast carcinoma , 2003, Cancer.