The Role of B7-H4 in Tumor Vaccine

Study Overview
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Brief Summary
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Glioma patients have poor prognosis because of limited choices of treatment. Therapeutic cancer vaccines have been proved to improve survival in glioma, but resistance is a new challenge for vaccine treatment, and the mechanism is unclear. The applicant found in previous papers that glioma cells induced B7-H4 overexpression in macrophages, and the expression level of B7-H4 is highly correlated with vaccine resistance. Preliminary experiments indicated that B7-H4 protein in macrophages inhibited the expression of ATF3, STAT1 and CXCL9/10, which also resulted in decreased T cell infiltration in glioma model of mouse and was a negative factor of vaccine benefits. Therefore, the applicant hypothesize that B7-H4 inhibits STAT1 transcription by reducing expression of ATF3, resulting in decreased phosphorylated-STAT1 in nucleus, which inhibiting expression and secretion of chemokines 9/10. Thereby, reduced infiltration of T cells in microenvironment will be followed, which ultimately promotes resistance of vaccine treatment in glioma. The follow-up plan of this project will be conducted based on the cells, organoid platform and animal experiments to confirm the role and mechanism of macrophage-derived B7-H4 in secretion of chemokines for T cells and treatment resistance of vaccines. Moreover, the DC vaccine produced by team of the applicant will be used to assess the probability of reversing vaccine resistance when intervening B7-H4 axis. Finally, a model for evaluating clinical benefits from vaccine will be established based on data from clinical trials combining with expression of B7-H4 and clinicopathologic features. This study will provide new evidences for the treatment of cancer vaccines in gliomas.

Official Title
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The Role and Mechanism of B7-H4/ATF3 Axis From Glioma Associated Macrophages in Treatment Resistance of Cancer Vaccine

Conditions
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Glioma

Intervention / Treatment
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* Biological: tumor vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Inclusion Criteria: The patients with glioma in the Department of Neurosurgery of Huashan Hospital Affiliated to Fudan University who meet the following three conditions can be enrolled They were 18-80 years old, male and female; The pathological results of frozen section during operation were gliomas; Tissue (6 mm * 6 mm) can be used for cell sorting on the basis of not affecting clinical routine diagnosis; Sign informed consent. Exclusion Criteria: Patients who meet any of the following criteria will not be included in this study: Participants in other clinical trials; Pregnant women.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| glioma patients receiving conventional treatment<br>surgery+radiotherapy+chemotherapy | |
| glioma patients with tumor vaccine<br>surgery+radiotherapy+chemotherapy+tumor vaccine | Biological: tumor vaccine<br>* DC vaccine produced by the Team<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| IHC analysis | Different expression level of proteins (CD3,CD8,B7-H4 et.ac) in Gliomas with different grades and molecular subgroups (100 cases) will be measured using immunohistochemical. | 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Transcriptomics | The issues collected will be used for transcriptome sequencing to measure gene expression level. | 36 months | 
| Immunomics | The issues collected will be used for TCR/BCR sequencing to measure clonality of lymphocytes | 36 months | 
| Proteomics | The issues collected will be used for proteomic sequencing to measure gene expression level in protein | 36 months | 
| Radiomics | The features from images will be extracted using algorithm of Deep-learning or Radiomics | 36 months | 
| Genomics | The issues collected will be used for whole genome sequencing or whole exome sequencing to measure gene mutations. | 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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glioma, treatment resistance, immunotherapy, cancer vaccine, macrophage