RESUMO
Treatment of late-stage lung cancer has witnessed limited advances. In contrast to the tremendous efforts toward improving adaptive immunity, approaches to modulating innate immunity are relatively immature. As important innate immune cells, tumor-associated macrophages (TAMs) account for a substantial fraction of tumor-infiltrating lymphocytes, which not only reverses the immune-suppressive tumor microenvironment but also facilitates an adaptive immune response. In this study, we developed a tumor-specific MMP-2-responsive CD47 blockage (TMCB) strategy to enable effective cancer immunotherapy. Briefly, the matrix metalloproteinase-2 (MMP-2)-responsive self-assembly peptide specifically recognizes CD47, which is highly expressed in lung tumor cells. Second, the MMP-2-responsive self-assembly peptide is efficiently cleaved by MMP-2, which is overexpressed in the tumor microenvironment. Finally, the generated residual peptide naturally self-assembles into peptide-based nanofibers. The in situ constructed nanofibers inhibit the canonical CD47 "Do not eat me" signal expressed on tumor cells to promote phagocytosis of tumor cells by macrophages, which further induces effective antigen presentation and initiates T cell-mediated adaptive immune responses to inhibit tumor growth. Thus, we described a peptide-based TMCB strategy that induces both innate and adaptive immune systems to inhibit tumor growth.
Assuntos
Antígeno CD47 , Neoplasias , Humanos , Imunoterapia , Metaloproteinase 2 da Matriz , Neoplasias/patologia , Neoplasias/terapia , Peptídeos , Fagocitose , Microambiente TumoralRESUMO
Targeted immunomodulation through biomolecule-based nanostructures, especially to dendritic cells (DCs), holds great promise for effective cancer therapy. However, construction of high-performance agonist by mimicking natural ligand to activate immune cell signaling is a great challenge so far. Here, a peptide-based nanoagonist toward CD40 (PVA-CD40) with preorganized interfacial topological structure that activates lymph node DCs efficiently and persistently, achieving amplified immune therapeutic efficacy is described. The on-site fabrication of PVA-CD40 is realized through the click conjugation of two functional peptides including the "CD40 anchoring arm" and the "assembly-driving motor." The resultant polyvalent interface rapidly triggers the receptor oligomerization and downstream signaling. Strikingly, one shot administration of PVA-CD40 elicits maturation period of DCs up to 2.3-fold comparing to that of CD40 antibody. Finally, combining the PVA-CD40 with anti-PD-1 antibody results in subsequent inhibition of tumor growth in both B16F10 and 4T1 mice tumor models with survival rate up to 37%, while none of the mice survives in the clinically relevant CD40 mAb and anti-PD-1 combination-treated group. It is envisioned that the fabrication of antibody-like superstructures in vivo provides an efficient platform for modulating the duration of immune response to achieve optimal therapeutic efficacy.
Assuntos
Células Dendríticas , Neoplasias , Animais , Antígenos CD40 , Imunoterapia/métodos , Camundongos , Neoplasias/tratamento farmacológico , Peptídeos/farmacologiaRESUMO
Tumor cells intensively engage in metabolic reprogramming for enhancing the availability of glycolytic metabolites and support cell proliferation. As the most important rate-limiting enzyme in aerobic glycolysis, activating the pyruvate kinase muscle isoform 2 (PKM2) from dimers to tetramers has become a key tumor chemotherapy method to control glucose metabolism. Herein, we developed a glycopeptide-based PKM2 nano-activator, which could induce the tetramerization of PKM2 based on serine bonding to Domain C of PKM2. The bound and trapped PKM2 tetramers significantly hindered glycolytic intermediates, prevented the nucleus translocation of dimeric PKM2, and ultimately inhibited the proliferation, chemoresistance and metastasis of tumor. The glycopeptide assembled into nanoparticles under aqueous conditions and in the circulation, which in situ transformed into PKM2 nano-activator with nanofibrillar structure after specifically activated by O-GlcNAcase recognition upregulated in a wide range of human tumors. Moreover, the glycopeptide-based PKM2 nano-activator successfully accumulated at the tumor sites and boosted the chemo-drug sensitivity against prostate and breast cancers. Attributed to these intriguing results, the newly developed glycopeptide-based PKM2 nano-activator can be envisioned a promising candidate for the treatment of tumors by switching catabolic pathways.
Assuntos
Neoplasias da Mama , Piruvato Quinase , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Glicólise , Glicopeptídeos/metabolismo , Humanos , Masculino , Músculos/metabolismo , Isoformas de Proteínas/metabolismo , Piruvato Quinase/metabolismoRESUMO
Life is recognized as a sophisticated self-assembling material system. Cancer involves the overexpression and improper self-assembly of proteins, such as cytoskeleton protein vimentin, an emerging target related to tumor metastasis. Herein, we design a binding-induced fibrillogenesis (BIF) peptide that in situ forms fibrous networks, blocking the improper self-assembly of vimentin against cancer. The BIF peptide can bind to vimentin and subsequently perform fibrillogenesis to form fibers on vimentin. The resultant peptide fibrous network blocks vimentin skeletonization and inhibits the migration and invasion of tumor cells. In mouse models of tumor metastasis, the volume of tumor and the number of lung metastases are markedly decreased. Moreover, the efficacy of BIF peptide (5 mg/kg) is much higher than small molecular antimetastasis drug withaferin A (5 mg/kg) as a standard, indicating that the BIF peptide shows advantages over small molecular inhibitors in blocking the intracellular protein self-assembly.
Assuntos
Neoplasias da Mama , Animais , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Movimento Celular , Feminino , Humanos , Camundongos , Peptídeos , Vimentina/genéticaRESUMO
One of the major challenges of immune checkpoint blockade (ICB) is the poor penetration of antibody for solid tumor treatment. Herein, peptides with deeper penetration capability are used to develop a click reaction-assisted peptide immune checkpoint blockade (CRICB) strategy that could in situ construct assemblies, enabling enhanced accumulation and prolonged PD-L1 occupancy, ultimately realizing high-performance tumor inhibition. First, the free DBCO-modified targeting peptide (TP) efficiently recognizes and binds PD-L1 in a deep solid tumor. Upon a reagent-free click reaction with a subsequently introduced azide-tethered assembled peptide (AP), the click reaction results in spontaneous self-aggregation in situ with enhanced accumulation and prolonged occupancy. In addition, the penetration of TP-AP (121.2 ± 15.5 µm) is significantly enhanced compared with that of an antibody (19.9 ± 5.6 µm) in a solid tumor tissue. More importantly, significant immunotherapy effects and negligible side effects are observed in 4T1 and CT26 tumor-bearing mice models treated with TP-AP, suggesting the high-performance tumor inhibition attributed to the CRICB strategy. In summary, this CRICB strategy manifest the preferable effects of immune checkpoint blockade, thereby extending the biomedical application of assembling peptides.
Assuntos
Anticorpos/farmacologia , Inibidores de Checkpoint Imunológico/farmacologia , Imunoterapia , Neoplasias Experimentais/terapia , Peptídeos/farmacologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Animais , Anticorpos/química , Linhagem Celular Tumoral , Feminino , Inibidores de Checkpoint Imunológico/química , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/imunologia , Imagem Óptica , Tamanho da Partícula , Peptídeos/química , Receptor de Morte Celular Programada 1/imunologia , Espectrometria de Fluorescência , Propriedades de SuperfícieRESUMO
Image-guided surgery plays a crucial role in realizing complete tumor removal, reducing postoperative recurrence and increasing patient survival. However, imaging of tumor lesion in the typical metabolic organs, e.g., kidney and liver, still has great challenges due to the intrinsic nonspecific accumulation of imaging probes in those organs. Herein, we report an in situ self-assembled near-infrared (NIR) peptide probe with tumor-specific excretion-retarded (TER) effect in tumor lesions, enabling high-performance imaging of human renal cell carcinoma (RCC) and achieving complete tumor removal, ultimately reducing postoperative recurrence. The NIR peptide probe first specifically recognizes αvß3 integrin overexpressed in renal cancer cells, then is cleaved by MMP-2/9, which is up-regulated in the tumor microenvironment. The probe residue spontaneously self-assembles into nanofibers that exhibit an excretion-retarded effect in the kidney, which contributes to a high signal-to-noise (S/N) ratio in orthotopic RCC mice. Intriguingly, the TER effect also enables precisely identifying eye-invisible tiny lesions (<1 mm), which contributes to complete tumor removal and significantly reduces the postoperative recurrence compared with traditional surgery. Finally, the TER strategy is successfully employed in high-performance identification of human RCC in an ex vivo kidney perfusion model. Taken together, this NIR peptide probe based on the TER strategy is a promising method for detecting tumors in metabolic organs in diverse biomedical applications.