Applying Osteosarcoma Immunology to Understand Disease Progression and Assess Immunotherapeutic Response

Pratt, Hillary G; Justin, Elser; Lindsey, Brock A.

doi:10.1007/978-3-030-43085-6_6

Cited by 15 publications

(23 citation statements)

References 100 publications

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“…There is evidence that OS is an immunogenic tumor [ 26 ]. Due to the prominence of the immune system in OS disease progression, understanding the OS immune system is crucial in treatment optimization and prognosis improvement in patients [ 27 ]. Tfh cells are major effector T cell divisions, which play an important role in inducing antibody production and B cell differentiation [ 12 , 28 ].…”

Section: Discussionmentioning

confidence: 99%

Abnormal Function of Circulating Follicular Helper T Cells Leads to Different Manifestations of B Cell Maturation and Differentiation in Patients with Osteosarcoma

Zhao

Liang

Cao

et al. 2022

Journal of Healthcare Engineering

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Objective. The objective of this study is to investigate the effect of dysfunctional circulating follicular helper T cells (Tfh) on B cell maturation and differentiation in patients with osteosarcoma (OS). Method. Data from 30 OS patients who underwent diagnosis and treatment in our hospital, as well as those of 30 healthy subjects (HC), were collected at the same time. Flow cytometry was employed to identify proportions of CD4+CXCR5+Tfh cells and Tfh cell subtypes Tfh17, Tfh1, and Tfh2 in the patient’s peripheral blood. CD40 L and IFNγ levels were detected after stimulating Tfh cells with an influenza antigen; the positive rates of CD27 and CD38 in B cells were detected before and after coculture with Tfh cells. qRT-PCR was carried out for Blimp-1 expression in B cells, and ELISA was employed to identify the levels of IgM, IgG, and IgA in B cells and IL-2, IL-10, and IL-4 in Tfh cells before and after coculture. Results. The percentage of CD4+CXCR5+Tfh cells in OS patients’ peripheral blood increased significantly. The Tfh cell ratio increased along with the TNM stage, and the Tfh cell ratio in OS metastasis patients is greater than that in nonmetastatic patients. In addition, Tfh2 and Tfh17 cells increased drastically in OS patients, and no meaningful change was seen in Tfh1 cells. CD40 L levels of Tfh cells in OS patients were less than those of the HC group, and IFNγ was substantially increased. After coculturing the OS group’s B cells with Tfh cells, the CD27+ and CD38+ cells of B cells were drastically greater, and Blimp-1 expression was also significantly increased. In addition, the levels of IL-21, IL-4, and IL-10 of Tfh cells in the OS group and the levels of IgA, IgG, and IgM in B cells were significantly reduced after coculture. Conclusion. Dysfunctional Tfh in OS patients can severely inhibit B cell development, maturation, and differentiation.

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Section: Discussionmentioning

confidence: 99%

Abnormal Function of Circulating Follicular Helper T Cells Leads to Different Manifestations of B Cell Maturation and Differentiation in Patients with Osteosarcoma

Zhao

Liang

Cao

et al. 2022

Journal of Healthcare Engineering

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“…Immunophenotypic analysis can be used as a very powerful tool to help better understand the complexity of immune response in osteosarcoma and the use of immunotherapy in this malignant tumor [ 26 ]. We analyzed the TIICs and TME of different CS subtypes and confirmed that CS showed the highest proportion of plasma cells and CD8 T cells and activated CD4 memory T cells and the highest stromal score, immune score, and comprehensive TME score.…”

Section: Discussionmentioning

confidence: 99%

Subtype Classification and Prognosis Signature Construction of Osteosarcoma Based on Cellular Senescence-Related Genes

Wang

Liu

Wang

et al. 2022

Journal of Oncology

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Background. Cellular senescence (CS) is an alternative procedure that replaces or reinforces inadequate apoptotic responses and is used as an influencing factor for a variety of cancers. The value of CS gene in evaluating the immunotherapy response and clinical outcome of osteosarcoma (OS) has not been reported, and an accurate risk model based on CS gene has not been developed for OS patients. Methods. 279 CS genes were obtained from CellAge. Univariate Cox regression analysis was used to screen the CS gene which was significantly related to the prognosis of OS samples in TARGET data set. The prognosis, clinicopathological features, immune infiltration, gene expression at immune checkpoints, tumor immune dysfunction and exclusion (TIDE) score, and chemotherapy resistance of OS were analyzed among clusters. Least absolute shrinkage and selection operator (Lasso) Cox regression analysis to build cellular senescence-related gene signature (CSRS). Univariate and multivariate Cox regression analysis of CSRS and clinical parameters were carried out, and the parameters with independent prognostic value were used to construct nomogram. Results. Based on 30 CS genes related to OS prognosis, OS samples were divided into three clusters: C1, C2, and C3. C3 showed the lowest survival rate and metastasis rate and the highest immune score and stromal score and was more likely to respond to immune checkpoint blockade (ICB) treatment. A CSRS scoring system including four CS genes (MYC, DLX2, EPHA3, and LIMK1) was constructed, which could distinguish the survival outcome, tumor microenvironment (TME) status, and ICB treatment response of patients with different CSRS score. Nomogram constructed by CSRS score and metastatic has a high prognostic value for OS. Conclusions. Our study identified a molecular classification determined by CS-related genes and developed a new CSRS that has potential value in OS immunotherapy response and clinical outcome prediction.

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“…Immunotherapy has been successful in a variety of malignant tumors, including lung cancer, and several immunotherapy drugs have been approved by the Food and Drug Administration (FDA) [22,23]. However, the application of immunotherapy in OS has been slow due to the complexity of the immune system and the subtle differences in the tumor-speci c microenvironment as well as the fact that the tumor itself may resist immunotherapy in various ways [24]. It is necessary to determine predictive biomarkers with higher sensitivity and speci city to stratify patients to maximize the bene ts for patients.…”

Section: Discussionmentioning

confidence: 99%

Identification of MAP3K15 as a Potential Prognostic Biomarker and Correlation with Immune Infiltrates in Osteosarcoma

Chen¹,

Kong²,

Cai³

et al. 2021

Preprint

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Background: Osteosarcoma (OS) is a type of primary malignant tumor, and increasing amounts of evidence show the clinical benefits of immunotherapy in treating OS. However, the lack of comprehensive studies on the complex OS immune microenvironment hinders the application of immunotherapy. Thus, we aimed to systematically study the immune characteristics of OS and identify novel biomarkers for OS treatment.Methods: We systematically studied the immune score and proportion of infiltrating immune cells in OS in the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) and Gene Expression Omnibus (GEO) databases using the ESTIMATE and CIBERSORT algorithms. Differential expression and functional analyses were used to identify dysregulated genes and explore their functions. Survival and Cox regression analyses were applied to establish an immune-related prognostic signature. The expression of MAP3K15 was performed by qPCR assay and immunohistochemistry. We divided 48 patients into high expression and low expression groups according to MAP3K15 expression.Results: A total of 103 differentially expressed immune genes (DEIGs) were found in the TARGET-OS and GSE39058 databases, and these DEIGs were mainly enriched in leukocyte proliferation, leukocyte differentiation, osteoclast differentiation, natural killer (NK) cell-mediated cytotoxicity and the adaptive immune system. A predictive signature was constructed based on the survival analysis, with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.65. Moreover, we found that mitogen-activated protein kinase kinase kinase 15 (MAP3K15) can predict the prognosis of patients with OS and is closely related to CD4 T cells, M0 macrophages, and M1 macrophages. We found that patients with high MAP3K15 expression had a significantly poorer prognosis Conclusions: Our study found that MAP3K15, whose expression level is closely related to immune activity in tumors, was a critical immune-related biomarker and may provide a basis for OS immunotherapy. Clinical Trial RegistrationNot applicable.

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Applying Osteosarcoma Immunology to Understand Disease Progression and Assess Immunotherapeutic Response

Cited by 15 publications

References 100 publications

Abnormal Function of Circulating Follicular Helper T Cells Leads to Different Manifestations of B Cell Maturation and Differentiation in Patients with Osteosarcoma

Abnormal Function of Circulating Follicular Helper T Cells Leads to Different Manifestations of B Cell Maturation and Differentiation in Patients with Osteosarcoma

Subtype Classification and Prognosis Signature Construction of Osteosarcoma Based on Cellular Senescence-Related Genes

Identification of MAP3K15 as a Potential Prognostic Biomarker and Correlation with Immune Infiltrates in Osteosarcoma

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