MAPK as target of glioma immunoediting by CD8 T-cells, and predictor of response to immunotherapy

MAPK 作为 CD8 T 细胞神经胶质瘤免疫编辑的靶点以及免疫治疗反应的预测因子

• 批准号: 9981297
• 负责人: Adam M Sonabend
• 金额: $ 37.13万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9981297
• 关键词: BRAF gene; Blood - brain barrier anatomy; CAR T cell therapy; CD8-Positive T-Lymphocytes; Cell Line; Cells; Characteristics; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Development; Exhibits; Flow Cytometry; Gene Expression; Genetic; Glioblastoma; Glioma; Human; ITGAM gene; Image; Immune; Immunocompetent; Immunohistochemistry; Immunotherapy; Implant; Infiltration; Inflammatory; Knock-out; Knockout Mice; MAP Kinase Gene; MAPK Signaling Pathway Pathway; Microglia; Modeling; Molecular; Mus; Mutation; Neoplasm Transplantation; PD-1 blockade; PTPN11 gene; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Phosphorylation; Platelet-Derived Growth Factor; Process; Recurrence; Reporting; Resistance; Role; Signal Transduction; Specimen; Stains; Study models; T cell response; T-Cell Depletion; T-Lymphocyte; Therapeutic; Transgenic Mice; Transgenic Model; Transplantation; Tumor Immunity; Tumor-associated macrophages; Tumor-infiltrating immune cells; Up-Regulation; base; chemokine; chimeric antigen receptor T cells; genetic approach; glioma cell line; immunogenic; macrophage; neoplastic cell; novel; p38 Mitogen Activated Protein Kinase; patient response; patient subsets; predicting response; programmed cell death protein 1; randomized trial; response; tumor; tumor progression

SUMMARY Whereas randomized trials for PD1 blockade in glioblastoma (GBM) are negative,2 a subset of these patients do respond to immunotherapy.3 Determining the basis of response will result in immunotherapy being effectively used for some patients. We recently reported the analysis of 66 recurrent GBM patients that were treated with PD1 blockade.1 Whereas response was defined based on imaging criteria, responsive patients exhibited significant increased survival that was independent of clinical characteristics or additional treatments. 30% of tumors of responsive patients had enrichment of BRAF and PTPN11 activating mutations, which stimulate MAPK pathway signaling.1 Therefore, molecular indicators of response to PD1 blockade for the majority of patients remain unidentified. We performed immunohistochemistry for phosphorylation of p38 and ERK, two effectors of this pathway. Extent of positivity for these markers was predictive of overall survival following PD1 blockade. Of relevance to our patient tumor studies, we modeled the effect of CD8 T-cell depletion on tumor progression on mouse transgenic gliomas that develop de novo. In this setting, CD8 T-cell depletion resulted in immunogenic tumors that upon transplantation, preferentially engrafted in recipients with CD8 T-cell depletion as opposed to immunocompetent hosts. Gliomas generated in the absence of CD8 T-cells showed upregulation of Braf and Ptpn11, and associated MAPK activation indicated by phosphorylation of p38 and Erk. CD8 T-cell depletion during glioma development also led to robust increase in tumor associated macrophages/microglia (TAM), and gene expression of pro-inflammatory TAM. MAPK activity correlated with TAM markers in mouse transgenic gliomas and human GBM, and with several chemokines that promote pro-inflammatory TAM. A CRISPR knock- out screen for the kinome on intracranial gliomas also implicated MAPK in T-cell recognition of tumor cells. These findings suggest that MAPK activity in tumor cells (that is suppressed by CD8 T-cells during glioma progression), promotes pro-inflammatory TAM. We hypothesize that GBM with elevated MAPK signaling, are more susceptible to CD8 T-cell recognition, as this pathway promotes anti-tumoral TAM. Thus, the subset of GBM that have MAPK signaling are susceptible to PD1 blockade and CAR T-cell immunotherapy. To investigate this, we will SA1) Determine the effects of CD8 T-cell depletion during glioma development on TAM phenotype. SA 2) Determine whether MAPK signaling promotes anti-tumoral glioma TAM. SA 3) Determine the effect of modulating glioma MAPK signaling on response to PD1 blockade and CAR T-cell therapy. We will use transgenic models in which tumors develop de novo, cell lines with varying levels of MAPK activation, genetic MAPK manipulation as well as clinically available drugs inhibit and/or promote MAPK signaling that cross the blood-brain barrier. Successful execution of these studies will establish a novel immune-related role of MAPK signaling in glioma. We will determine whether MAPK signaling by tumor cells influences response to PD1 blockade, and CAR T-cell therapy.

总结