Immunogenic Senescence Sensitizes Lung Cancer to LUNX-Targeting Therapy
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA768280 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16173354_1.fastq.gz | Fastqsanger.gz | |||
| SRR16173354_2.fastq.gz | Fastqsanger.gz | |||
| SRR16173355_1.fastq.gz | Fastqsanger.gz | |||
| SRR16173355_2.fastq.gz | Fastqsanger.gz | |||
| SRR16173356_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 24 |
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Project description:Immunogenic Senescence Sensitizes Lung Cancer to LUNX-Targeting Therapy [A549]
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Project description:Immunogenic Senescence Sensitizes Lung Cancer to LUNX-Targeting Therapy [NCI-H292]
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Project description:The higher immunogenicity of tumors usually predicts favorable therapeutic responses. Tumor antigens dominate the immunogenic character within tumors. We investigated if there was a targetable tumor antigen during immunogenic chemotherapy within lung cancer. Chemotherapy-induced immunogenic senescence was demonstrated using a multi-marker, three-step workflow and RNA-sequencing data. The ability of anti-lung-specific X protein (LUNX) antibody to suppress the survival of senescent lung cancer cells was evaluated in vitro and in vivo using real-time cytotoxicity analysis and xenograft mouse models, respectively. The induction of cellular senescence by immunogenic chemotherapy boosted cell-surface shuttling of LUNX and enhanced the immunogenic features of senescent tumor cells, which sensitized lung cancer cells to anti-LUNX antibody-mediated therapy and contributed to tumor suppression. The immunogenic senescence-mediated anti-tumor response was triggered by the direct action of antibody on tumor cells, strengthened by natural-killer cells through an antibody-dependent cell-mediated cytotoxicity response and, ultimately, led to tumor control. Our findings suggest that LUNX is a lung cancer targetable-immunogenic antigen. The proportion of lung cancers responding to LUNX-targeting therapy could be expanded substantially by immunogenic chemotherapy that induces senescence-associated translocation of LUNX to the plasma membrane.
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Project description:The higher immunogenicity of tumors usually predicts favorable therapeutic responses. Tumor antigens dominate the immunogenic character within tumors. We investigated if there was a targetable tumor antigen during immunogenic chemotherapy within lung cancer. Chemotherapy-induced immunogenic senescence was demonstrated using a multi-marker, three-step workflow and RNA-sequencing data. The ability of anti-lung-specific X protein (LUNX) antibody to suppress the survival of senescent lung cancer cells was evaluated in vitro and in vivo using real-time cytotoxicity analysis and xenograft mouse models, respectively. The induction of cellular senescence by immunogenic chemotherapy boosted cell-surface shuttling of LUNX and enhanced the immunogenic features of senescent tumor cells, which sensitized lung cancer cells to anti-LUNX antibody-mediated therapy and contributed to tumor suppression. The immunogenic senescence-mediated anti-tumor response was triggered by the direct action of antibody on tumor cells, strengthened by natural-killer cells through an antibody-dependent cell-mediated cytotoxicity response and, ultimately, led to tumor control. Our findings suggest that LUNX is a lung cancer targetable-immunogenic antigen. The proportion of lung cancers responding to LUNX-targeting therapy could be expanded substantially by immunogenic chemotherapy that induces senescence-associated translocation of LUNX to the plasma membrane.
2024-10-03 | GSE185208 | GEO
Project description:The higher immunogenicity of tumors usually predicts favorable therapeutic responses. Tumor antigens dominate the immunogenic character within tumors. We investigated if there was a targetable tumor antigen during immunogenic chemotherapy within lung cancer. Chemotherapy-induced immunogenic senescence was demonstrated using a multi-marker, three-step workflow, and RNA-sequencing data. The ability of anti-lung-specific X protein (LUNX) antibody to suppress the survival of senescent lung cancer cells was evaluated in vitro and in vivo using real-time cytotoxicity analysis and xenograft mouse models, respectively. The induction of cellular senescence by immunogenic chemotherapy boosted cell-surface shuttling of LUNX and enhanced the immunogenic features of senescent tumor cells, which sensitized lung cancer cells to anti-LUNX antibody-mediated therapy and contributed to tumor suppression. The immunogenic senescence-mediated anti-tumor response was triggered by the direct action of antibody on tumor cells, strengthened by natural-killer cells through an antibody-dependent cell-mediated cytotoxicity response, and ultimately, led to tumor control. Our findings suggest that LUNX is a lung cancer targetable-immunogenic antigen. The proportion of lung cancers responding to LUNX-targeting therapy could be expanded substantially by immunogenic chemotherapy that induces senescence-associated translocation of LUNX to the plasma membrane.
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Project description:Cellular senescence is a stress response that activates innate immunity. However, the interplay between senescent cells and the adaptive immune system remains largely unexplored. Here, we show that senescent cells display enhanced MHC class I (MHC-I) antigen processing and presentation. Immunization of mice with senescent syngeneic fibroblasts generates CD8 T cells reactive against both normal and senescent fibroblasts, some of them targeting senescence-associated MHC-I-peptides. In the context of cancer, we demonstrate that senescent cancer cells trigger strong anti-tumor protection mediated by antigen-presenting cells and CD8 T cells. This response is superior to the protection elicited by cells undergoing immunogenic cell death. Finally, induction of senescence in patient-derived cancer cells exacerbates the activation of autologous tumor-reactive CD8 tumor-infiltrating lymphocytes (TILs) with no effect on non-reactive TILs. Our study indicates that immunization with senescent cancer cells strongly activates anti-tumor immunity, and this can be exploited for cancer therapy.
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Project description:Standard cancer therapy targets tumor cells without considering the possible collateral damage on the tumor microenvironment that could impair therapy response. Employing patient-derived tumor organoids and primary stroma cells or a novel murine rectal cancer model, we show that interleukin-1 (IL-1 dependent inflammatory cancer-associated fibroblast (iCAF) polarization triggers oxidative DNA damage in iCAFs leading to p53-mediated therapy-induced senescence associated with changes in matrisome composition, chemoradiotherapy resistance and disease progression. IL-1 inhibition, prevention of iCAF senescence or senolytic therapy sensitizes mice to irradiation. In rectal cancer patients a dominant iCAF gene signature as well as lower IL-1 receptor antagonist (IL-1RA) serum levels correlate with poor prognosis. Moreover, conditioned supernatant from patient tumor organoids renders fibroblasts susceptible to radiation-induced senescence in an IL-1-dependent manner. Collectively, we unravel a critical role for iCAFs in therapy resistance and identify IL-1 signaling as an attractive target for stroma-repolarization and prevention of CAF senescence.
2022-02-08 | PXD020871 | Pride
Project description:Standard cancer therapy targets tumor cells without considering the possible collateral damage on the tumor microenvironment that could impair therapy response. Employing patient-derived tumor organoids and primary stroma cells or a novel murine rectal cancer model, we show that interleukin-1a (IL-1a) dependent inflammatory cancer-associated fibroblast (iCAF) polarization triggers oxidative DNA damage in iCAFs leading to p53-mediated therapy-induced senescence associated with changes in matrisome composition, chemoradiotherapy resistance and disease progression. IL-1 inhibition, prevention of iCAF senescence or senolytic therapy sensitizes mice to irradiation. In rectal cancer patients a dominant iCAF gene signature as well as lower IL-1 receptor antagonist (IL-1RA) serum levels correlate with poor prognosis. Moreover, conditioned supernatant from patient tumor organoids renders fibroblasts susceptible to radiation-induced senescence in an IL-1-dependent manner. Collectively, we unravel a critical role for iCAFs in therapy resistance and identify IL-1 signaling as an attractive target for stroma-repolarization and prevention of CAF senescence.
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