Targeting cathepsin B by cycloastragenol enhances anti-tumor immunity via inhibiting MHC-1 degradation and promoting the presentation of tumor antigen
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE197229 | GEO | 2023/02/22
REPOSITORIES: GEO
Similar Datasets
Project description:Purpose:We want to elaborate the specific mechanism of CAG inhibiting the growth of transplanted mouse colon cancer cell MC38. Methods:After MC38 cells were inoculated into C57BL/6 mice for 6 days, the mice were evenly divided into PBS group and CAG group, and PBS and CAG (50mg / kg) were administered by gavage every day. On the 18th day, the mouse tumors were removed, and one tumor was selected to prepare single cell suspension for 10x-scRNA-seq and 10x-scATAC-seq. Results:We found that CAG promoted the antigen-presenting function of tumor cells and enhanced the killing ability of CD8 T cells. Conclusions:CAG enhances the antitumor immunity of CD8 T cells by promoting the antigen presentation of tumor cells.
2023-02-22 | GSE197228 | GEO
Project description:Purpose:We want to elaborate the specific mechanism of CAG inhibiting the growth of transplanted mouse colon cancer cell MC38. Methods:After MC38 cells were inoculated into C57BL/6 mice for 6 days, the mice were evenly divided into PBS group and CAG group, and PBS and CAG (50mg / kg) were administered by gavage every day. On the 18th day, the mouse tumors were removed, and one tumor was selected to prepare single cell suspension for 10x-scRNA-seq and 10x-scATAC-seq. Results:We found that CAG promoted the antigen-presenting function of tumor cells and enhanced the killing ability of CD8 T cells. Conclusions:CAG enhances the antitumor immunity of CD8 T cells by promoting the antigen presentation of tumor cells.
2023-02-22 | GSE197227 | GEO
Project description:BackgroundThe loss of tumor antigens and depletion of CD8 T cells caused by the PD-1/PD-L1 pathway are important factors for tumor immune escape. In recent years, there has been increasing research on traditional Chinese medicine in tumor treatment. Cycloastragenol (CAG), an effective active molecule in Astragalus membranaceus, has been found to have antiviral, anti-aging, anti-inflammatory, and other functions. However, its antitumor effect and mechanism are not clear.MethodsThe antitumor effect of CAG was investigated in MC38 and CT26 mouse transplanted tumor models. The antitumor effect of CAG was further analyzed via single-cell multiomics sequencing. Target responsive accessibility profiling technology was used to find the target protein of CAG. Subsequently, the antitumor mechanism of CAG was explored using confocal microscopy, coimmunoprecipitation and transfection of mutant plasmids. Finally, the combined antitumor effect of CAG and PD-1 antibodies in mice or organoids were investigated.ResultsWe found that CAG effectively inhibited tumor growth in vivo. Our single-cell multiomics atlas demonstrated that CAG promoted the presentation of tumor cell-surface antigens and was characterized by the enhanced killing function of CD8+ T cells. Mechanistically, CAG bound to its target protein cathepsin B, which then inhibited the lysosomal degradation of major histocompatibility complex I (MHC-I) and promoted the aggregation of MHC-I to the cell membrane, boosting the presentation of the tumor antigen. Meanwhile, the combination of CAG with PD-1 antibody effectively enhanced the tumor killing ability of CD8+ T cells in xenograft mice and colorectal cancer organoids.ConclusionOur data reported for the first time that cathepsin B downregulation confers antitumor immunity and explicates the antitumor mechanism of natural product CAG.
| S-EPMC9621195 | biostudies-literature
Project description:Targeting cathepsin B by cycloastragenol enhances anti-tumor immunity via inhibiting MHC-1 degradation and promoting the presentation of tumor antigen
| PRJNA809393 | ENA
Project description:Targeting cathepsin B by cycloastragenol enhances anti-tumor immunity via inhibiting MHC-1 degradation and promoting the presentation of tumor antigen [ATAC-seq]
| PRJNA809397 | ENA
Project description:Targeting cathepsin B by cycloastragenol enhances anti-tumor immunity via inhibiting MHC-1 degradation and promoting the presentation of tumor antigen [RNA-seq]
| PRJNA809396 | ENA
Project description:For a successful anti-cancer vaccine, antigen presentation on the major histocompatibility complex (MHC) class I is a requirement. To accomplish this, an antigen must be delivered to the cytoplasm by overcoming the endosome/lysosome. We previously reported that a lipid nanoparticle modified with a KALA peptide (WEAKLAKALAKALAKHLAKALAKALKA), an α-helical cationic peptide, permits the encapsulated pDNA to be efficiently delivered to the cytoplasm in bone marrow-derived dendritic cells (BMDCs). Herein, we report on the use of KALA-modified liposomes as an antigen carrier, in an attempt to induce potent antigen-specific cellular immunity. The subcutaneous injection of KALA-modified ovalbumin (OVA)-encapsulating liposomes (KALA-OVA-LPs) elicited a much more potent OVA-specific cytotoxic T lymphocyte activity and anti-tumor effect in comparison with particles that were modified with octa-arginine (R8), a cell-penetrating peptide (R8-OVA-LPs). In addition, the numbers of OVA-specific CD8+ T cells were increased by immunization the KALA-OVA-LPs. The treatment of BMDCs with KALA-OVA-LPs induced a substantial MHC class I antigen presentation. Furthermore, the acidic pH-dependent membrane destabilization activity of KALA-OVA-LPs strongly suggests that they are able to escape from endosomes/lysosomes and thereby deliver their cargos to the cytoplasm. Collectively, the KALA-modified liposome is a potential antigen delivery platform for use as a protein vaccine.
| S-EPMC5383577 | biostudies-literature
Project description:Bifunctional degraders, also referred to as proteolysis-targeting chimeras (PROTACs), are a recently developed class of small molecules. They were designed to specifically target endogenous proteins for ubiquitin/proteasome-dependent degradation and to thereby interfere with pathological mechanisms of diseases, including cancer. In this study, we hypothesized that this process of acute pharmacologic protein degradation might increase the direct MHC class I presentation of degraded targets. By studying this question, we contribute to an ongoing discussion about the origin of peptides feeding the MHC class I presentation pathway. Two scenarios have been postulated: peptides can either be derived from homeostatic turnover of mature proteins and/or from short-lived defective ribosomal products (DRiPs), but currently, it is still unclear to what ratio and efficiency both pathways contribute to the overall MHC class I presentation. We therefore generated the intrinsically stable model antigen GFP-S8L-F12 that was susceptible to acute pharmacologic degradation via the previously described degradation tag (dTAG) system. Using different murine cell lines, we show here that the bifunctional molecule dTAG-7 induced rapid proteasome-dependent degradation of GFP-S8L-F12 and simultaneously increased its direct presentation on MHC class I molecules. Using the same model in a doxycycline-inducible setting, we could further show that stable, mature antigen was the major source of peptides presented, thereby excluding a dominant role of DRiPs in our system. This study is, to our knowledge, the first to investigate targeted pharmacologic protein degradation in the context of antigen presentation and our data point toward future applications by strategically combining therapies using bifunctional degraders with their stimulating effect on direct MHC class I presentation.
| S-EPMC5766668 | biostudies-literature
Project description:PurposeDespite the accumulation of extensive genomic alterations, many cancers fail to be recognized as "foreign" and escape destruction by the host immune system. Immunotherapies designed to address this problem by directly stimulating immune effector cells have led to some remarkable clinical outcomes, but unfortunately, most cancers fail to respond, prompting the need to identify additional immunomodulatory treatment options.Experimental Design: We elucidated the effect of a novel treatment paradigm using sustained, low-dose HSP90 inhibition in vitro and in syngeneic mouse models using genetic and pharmacologic tools. Profiling of treatment-associated tumor cell antigens was performed using immunoprecipitation followed by peptide mass spectrometry.ResultsWe show that sustained, low-level inhibition of HSP90 both amplifies and diversifies the antigenic repertoire presented by tumor cells on MHC-I molecules through an IFNγ-independent mechanism. In stark contrast, we find that acute, high-dose exposure to HSP90 inhibitors, the only approach studied in the clinic to date, is broadly immunosuppressive in cell culture and in patients with cancer. In mice, chronic non-heat shock-inducing HSP90 inhibition slowed progression of colon cancer implants, but only in syngeneic animals with intact immune function. Addition of a single dose of nonspecific immune adjuvant to the regimen dramatically increased efficacy, curing a subset of mice receiving combination therapy.ConclusionsThese highly translatable observations support reconsideration of the most effective strategy for targeting HSP90 to treat cancers and suggest a practical approach to repurposing current orally bioavailable HSP90 inhibitors as a new immunotherapeutic strategy.See related commentary by Srivastava and Callahan, p. 6277.
| S-EPMC6825536 | biostudies-literature
Project description:Tumor Associated Antigens (TAAs) may suffer from an immunological tolerance due to expression on normal cells. In order to potentiate their immunogenicity, heteroclitic peptides (htcPep) were designed according to prediction algorithms. In particular, specific modifications were introduced in peptide residues facing to TCR. Moreover, a MHC-optimized scaffold was designed for improved antigen presentation to TCR by H-2Db allele. The efficacy of such htcPep was assessed in C57BL/6 mice injected with syngeneic melanoma B16F10 or lung TC1 tumor cell lines, in combination with metronomic chemotherapy and immune checkpoint inhibitors. The immunogenicity of htcPep was significantly stronger than the corresponding wt peptide and the modification involving both MHC and TCR binding residues scored the strongest. In particular, the H-2Db-specific scaffold significantly potentiated the peptides' immunogenicity and control of tumor growth was comparable to wt peptide in a therapeutic setting. Overall, we demonstrated that modified TAAs show higher immunogenicity compared to wt peptide. In particular, the MHC-optimized scaffold can present different antigen sequences to TCR, retaining the conformational characteristics of the corresponding wt. Cross-reacting CD8+ T cells are elicited and efficiently kill tumor cells presenting the wild-type antigen. This novel approach can be of high clinical relevance in cancer vaccine development.
| S-EPMC8564487 | biostudies-literature