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Defining a cross-primed anti-tumor T cell signature to guide immunotherapy development

定义交叉引发的抗肿瘤 T 细胞特征来指导免疫疗法的开发

基本信息

批准号：
10537849
负责人：
Gabrielle Lubitz
金额：
$ 4.52万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-11 至 2025-07-10
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10537849
关键词：
Address Adoptive Transfer Agonist Allogenic Animal Model Antigen Presentation Antigen-Presenting Cells Antigens Autoantigens Automobile Driving Breast Cancer Model CD8-Positive T-Lymphocytes CXCL9 gene Cross Presentation Cross-Priming Dendritic Cells Development Exhibits FLT3 ligand Failure Flow Cytometry Immune response Immunologic Monitoring Immunotherapy Inbred BALB C Mice Interferon Type II Interleukin-12 Interleukin-2 Intrinsic factor Knock-out Luciferases Lymphoma Measures Mediating Methods Modeling Monitor Mus Mutation Outcome Outcome Study PD-1 blockade Patients Phenotype Radiation therapy Resistance Role T cell response T cell therapy T-Cell Activation T-Lymphocyte Techniques Tissues Tumor Antigens Tumor-infiltrating immune cells Vaccination anti-PD-1 antigen-specific T cells antitumor effect base cancer therapy chemokine cytotoxicity design effective therapy immune checkpoint blockade improved in situ vaccination in situ vaccine in vivo malignant breast neoplasm mouse model neoantigens neoplastic cell new therapeutic target novel patient subsets pre-clinical predicting response programs receptor recruit response success targeted treatment therapy design tool transcriptome sequencing transcriptomics treatment response tumor tumor growth

项目摘要

PROJECT SUMMARY/ABSTRACT Immunotherapies such as checkpoint blockade have revolutionized cancer therapy, but responses are seen only in a subset of patients. Though tumor-intrinsic factors such as tumor mutational burden (TMB) or IFNγ “inflamed” signature partially predict sensitivity to checkpoint blockade, these correlations are limited—most patients with “inflamed” tumors or high TMB still fail to respond. A critical step for efficacy of T cell-mediated immunotherapies, including checkpoint blockade, is dendritic cell cross-presentation of tumor antigen (Ag) to CD8+ T cells. Cross- presentation in vivo requires Batf3-expressing type 1 dendritic cells (cDC1), though these DC have additional functions, including secretion of T cell-recruiting chemokines, driving tumor-reactive T cell (TRT) responses. Because patients with cDC1-enriched tumors have improved responses to anti-PD1, we developed an in situ vaccination (ISV) combining FLT3L, radiotherapy (XRT), and TLR agonism to enhance cDC1 cross-priming of TRT and observed that ISV potentiated anti-tumor effects of PD1 blockade and induced systemic tumor regressions in treated patients. Additionally, we have shown that adoptive transfer of tumor-specific T cells into syngeneic RAG-/- mice clears tumors, while transfer into allogeneic RAG-/- mice fails to control tumor growth, highlighting that APC cross-priming of CD8+ T cells is required for efficacy of antitumor T cells. Despite the critical role of cDC1 cross-priming of CD8+ T cells for effective therapy, there is no established method for measuring T cell cross- or direct-priming in vivo. Consequently, there is a critical need for methods to directly measure CD8+ T cell cross-priming for identifying novel therapeutic targets to enhance cross-priming, and to understand mechanisms of therapy resistance. We hypothesize that cross- and direct-primed T cells, and ISV-primed vs untreated T cells, will harbor distinct signatures, mirroring their differential antitumor efficacy. In Aim 1, we will develop mouse models of cross- and direct-priming using H2Kd knockout, H2Kb-transfected, GFP/OVA- expressing lymphoma and breast cancers and transfer of Ag-specific T cells into syngeneic and allogeneic RAG-/- mice. We will sort tumor-reactive T cells and perform bulk RNA-seq and spectral flow cytometry to identify a cross-primed CD8+ T cell signature. In Aim 2, we will use bulk RNA-seq and spectral flow cytometry to characterize the T cell response to ISV and checkpoint blockade across tumors (lymphoma, breast cancer), model antigens (GFP, OVA, luciferase), and endogenous tumor antigens. The outcome of this study will be elucidation of a cross-primed CD8+ T cell phenotype and a novel immune monitoring technique that allows targeted design of novel immunotherapies by targeting novel checkpoints or costimulators to increase cross- priming of tumor-reactive T cells.

项目总结/文摘