MAGEA antigens as immunotherapeutic targets for advanced osteosarcoma
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ABSTRACT:
PROVIDER: PRJNA993578 | ENA |
REPOSITORIES: ENA
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Project description:Osteosarcoma is the most common primary bone sarcoma. About 50% of patients develop metastatic disease and their 5-year survival lingers at around 20-30%. T cell checkpoint blockade immunotherapies have revolutionized cancer treatment in the last decade, but their impact remains limited in osteosarcoma. In order to reveal potentially novel immunotherapeutic strategies for advanced osteosarcoma, we conducted an immunogenomic characterization of a unique sample set comprising multiple osteosarcoma samples from seven patients, collected throughout the progression of the disease. We performed RNA-sequencing and imaging mass cytometry analysis on those samples to reveal the immunological landscape during osteosarcoma progression. Transcriptional and phenotypical hallmarks of cytotoxic T cell-driven anti-cancer immunity were enriched in metastatic lesions as compared to primary tumors. In parallel, we found a pronounced increase in the expression of cancer testis antigens, particularly MAGEA-related antigens, in osteosarcoma metastases. Their overexpression in metastatic lesions was confirmed at protein level and positive expression of MAGEA3 in primary tumors showed a significant association with metastasis free survival. Importantly, we demonstrated the presentation of MAGE-derived peptides in three osteosarcoma cell lines. These findings indicate a concurrent augmentation of cytotoxic anti-tumor immune responses and expression of MAGEA antigens from primary to metastatic osteosarcoma. This observation warrants the exploration of MAGEA antigens as potential targets for immunotherapy in the treatment of advanced osteosarcoma.
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Project description:Despite the development of diagnostic and advanced treatment strategies, the prognosis of patients with osteosarcoma remains poor. A limited understanding of the pathogenesis of osteosarcomas has impeded any improvement in patient outcomes over the past 4 decades. It is thus urgent to identify novel effective targets and treatment regimens for osteosarcoma patients. In this study we delineated the super-enhancer landscape in osteosarcoma cells on the basis of H3K27ac signal intensity by ChIP-Seq and found that super-enhancer-associated genes contribute to the malignant potential of osteosarcoma. THZ2, a novel small molecular inhibitor, shows a powerful anti-osteosarcoma ability through suppress super-enhancer-associated genes selectively. Utilizing the characteristics of super-enhancers in cancer cells, we identified 5 critical super-enhancer-associated oncogenes. With the comparative and retrospective analysis in large numbers of human specimens from patients, these 5 oncogenes were observed closely related with patient prognosis. Our findings determined that targeting super-enhancer-associated oncogenes with transcriptional inhibitor, THZ2, was a promising therapeutic strategy in osteosarcoma, and provided novel candidate targets for patients with osteosarcoma.
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Project description:Background: Cancer testis antigens (CTAs) are an extensive gene family with a unique expression pattern restricted to testis tissues, but aberrantly high expressed in a variety of cancer tissues. In view of this, CTAs are typically considered as efficient biomarkers and targets of immunotherapy. However, limited information is available regarding CTAs as immunotherapeutic targets for gastric cancer (GC) patients. Herein, we evaluated the expression levels of CTAs in both Eastern and Western GC patients and elucidate the expression pattern and functions of a novel CTAs.
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Project description:Immunotherapy remains underexploited in AML compared to other hematological malignancies. Currently, gemtuzumab ozogamicin is the only therapeutic antibody approved for this disease. To identify potential targets for immunotherapeutic intervention, we analyzed the surface proteome of 100 genetically diverse primary human AML specimens for the identification of cell surface proteins and conducted single-cell transcriptome analysis on a subset of these specimens to assess antigen expression at the sub-population level. Through this comprehensive effort, we successfully identified numerous antigens and markers preferentially expressed by primitive AML cells. Many identified antigens are targeted by therapeutic antibodies currently under clinical evaluation for various cancer types, highlighting the potential therapeutic value of the approach. Importantly, this initiative led to the uncovering of AML heterogeneity at the surfaceome level, identifying several antigens and potential LSC markers characterising AML subgroups and positioning immunotherapy as a promising approach to target AML subgroup specificities.
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