Dataset Information

T cell exhaustion drives osteosarcoma pathogenesis.

ABSTRACT:

Background

Osteosarcoma (OS) is a rare cancer with a bimodal age distribution that peaks in children and young adults. It has been shown that the expression of programmed cell death protein 1 (PD-1) and programmed death ligand-1 (PD-L1) on tumor-infiltrating immune cells negatively correlates with prognosis of OS patients. However, a comprehensive assessment of the tumor-infiltrating immune cells in OS and their function has not been performed.

Methods

CD8⁺ T cells were isolated from biopsy tissue samples collected from OS patients and control subjects. Mass cytometry, Treg suppression assay, mixed lymphocyte reaction assay, and effector T cell functional assay were performed to analyze the function of tumor-infiltrating T cells. A xenograft metastasis model was established in BALB/c nude mice.

Results

Macrophages and CD3⁺ T cells comprised most of the tumor-infiltrating immune cells in OS, with a disproportionately higher number of helper CD4⁺ T cells than effector CD8⁺ T cells. Whereas the tumor-infiltrating regulatory T cells were functionally intact, the CD8⁺ T cells showed increased expression of the immune checkpoint receptor (ICR) PD-1 and T cell immunoglobulin and mucin-domain containing 3 (TIM3) and were functionally inactive. TIM3 blockade using a monoclonal antibody restored the T cell alloreactive function of the CD8⁺ T cells ex vivo. TIM3 blockade in a xenograft model of OS impaired tumor growth in vivo. TIM3 blockade decreased the number of tumor-infiltrating CD4⁺ T cells while increasing the numbers and functional activation of tumor-infiltrating CD8⁺ T cells in vivo.

Conclusions

These results highlight that TIM3 blockade might be a viable therapeutic option and should be tested in additional preclinical models.

SUBMITTER: Sun CY

PROVIDER: S-EPMC8506720 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Publications

T cell exhaustion drives osteosarcoma pathogenesis.

Sun Cheng-Ying CY Zhang Zhe Z Tao Lei L Xu Fei-Fei FF Li Hui-Yuan HY Zhang Hui-Yu HY Liu Wei W

Annals of translational medicine 20210901 18

<h4>Background</h4>Osteosarcoma (OS) is a rare cancer with a bimodal age distribution that peaks in children and young adults. It has been shown that the expression of programmed cell death protein 1 (PD-1) and programmed death ligand-1 (PD-L1) on tumor-infiltrating immune cells negatively correlates with prognosis of OS patients. However, a comprehensive assessment of the tumor-infiltrating immune cells in OS and their function has not been performed.<h4>Methods</h4>CD8<sup>+</sup> T cells were ...[more]

PMID: 34733999

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Project description:BackgroundMethylation-related signatures play crucial roles in tumorigenesis and progression. However, their roles in the immune response in primary glioblastoma (GBM) remains unclear.MethodsWe analyzed the differential expression of specific members of T cell exhaustion-related pathways in GBM from the perspective of T cell exhaustion. We further screened for significantly negatively correlated methylation sites as candidate methylation markers for T cell exhaustion. Using consensus clustering, we divided the samples into two categories with significant differences in overall survival (OS). We then performed univariate and multivariate Cox regression analyses to construct the T Cell Exhaustion Methylation (TEXM) signature. Finally, we confirmed that this signature served as an independent prognostic factor, and further characterized it in terms of drug resistance and immunotherapy.ResultsWe identified 95 significantly differentially expressed T cell exhaustion-related genes and 51 methylation markers associated with T cell exhaustion. The cancer samples were classified according to methylation site markers, thus indicating two subtypes with significant differences in OS: subtype A and subtype B. Tumor scores, stromal scores, tumor purity, and ESTIMATE scores all showed significant differences between subtypes (P < 0.05). Univariate Cox regression analysis identified five methylation sites significantly associated with OS, and multivariate Cox regression analysis was used to construct the TEXM signature model by using these five methylation sites. Significant differences in OS were found between the groups with high and low TEXM signature scores, on the basis of calculation of the TEXM signature scores of tumor samples and using the median score to divide them into high and low score groups. Survival analysis revealed that the high score group had poorer OS and DFS than the low score group in the validation set. Notably, we observed a significant difference in drug sensitivity between the high and low TEXM signature score groups, with the high score group showing higher drug resistance and poorer prognosis. The tumor immune state, as predicted with Tracking Tumor Immunophenotype (TIP), revealed significant differences in antitumor immune scores between the high and low TEXM signature score groups. Finally, we identified 43 significantly differentially regulated metabolism-associated biological processes.ConclusionThe epigenetic methylation-related TEXM signature plays a key role in driving differential immune responses in GBM.

Project description:BackgroundOsteosarcoma, an aggressive bone malignancy predominantly affecting children and adolescents, presents significant therapeutic challenges with a 5-year survival rate below 30% in metastatic cases. T-cell exhaustion, characterized by the overexpression of immune checkpoint molecules, contributes to osteosarcoma progression and immune evasion. Although targeting these inhibitory pathways has shown potential in restoring T-cell activity, the molecular regulators of T-cell depletion in osteosarcoma are poorly understood.MethodsThis study employed comprehensive bioinformatics analyses on osteosarcoma samples from the TARGET database, combined with normal tissue data from the GTEx database, to identify T-cell exhaustion-associated genes and their co-expressed long non-coding RNAs (lncRNAs). Gene ontology and KEGG pathway analyses were used to elucidate immune-related pathway enrichments. A six-lncRNA prognostic model was established using LASSO regression and validated in separate cohorts. Functional assays evaluated the impact of the lncRNA AL031775.1 on osteosarcoma cell behavior and T-cell function.ResultsTwenty-four key T-cell exhaustion-related genes were identified and significantly enriched in immune-related pathways, indicating their importance in the osteosarcoma immune microenvironment. The constructed six-lncRNA model stratified patients by survival prognosis, showing robust predictive performance across cohorts. Among the six identified lncRNAs, AL031775.1 is notably downregulated in osteosarcoma patients and significantly promotes osteosarcoma cell proliferation, migration, and invasion while contributing to T-cell exhaustion. In T cells, downregulation of AL031775.1 impairs antitumor immunity, upregulates immune checkpoint molecules LAG3, PD1, and CTLA4, and diminishes T-cell cytotoxic activity against tumor cells.ConclusionThis study identifies a novel six-lncRNA prognostic model and highlights the therapeutic potential of AL031775.1 in managing osteosarcoma by enhancing T-cell immunity and counteracting tumor progression. Targeting AL031775.1 represents a promising approach to improve immunotherapy efficacy in osteosarcoma. These findings provide critical insights into the molecular regulation of T-cell exhaustion and suggest a new avenue for therapeutic intervention.

Dataset Information

T cell exhaustion drives osteosarcoma pathogenesis.

Background

Methods

Results

Conclusions

Publications

T cell exhaustion drives osteosarcoma pathogenesis.

Similar Datasets

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