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Evaluation of T follicular regulatory cells as novel cellular targets of cancer immunotherapy

滤泡调节性 T 细胞作为癌症免疫治疗新细胞靶点的评估

基本信息

批准号：
10737557
负责人：
Simon Eschweiler
金额：
$ 10.25万
依托单位：
LA JOLLA INSTITUTE FOR IMMUNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10737557
关键词：
ATAC-seq Adoptive Transfer Affect Antibodies Antigens Antitumor Response Automobile Driving CD8-Positive T-Lymphocytes CTLA4 gene Cells Cellular immunotherapy Colitis Colon Combined Modality Therapy DNA Binding Data Development Dose Enhancers Epithelial Cells Evaluation Exhibits Frequencies Gene Expression Profile Generations Genes Genetic Engineering Genetic Transcription Half-Life Human Immune Immunology Immunosuppression Immunotherapy Impairment Infiltration Link Maintenance Malignant Neoplasms Modeling Molecular Mus Nature Neoadjuvant Therapy Non-Malignant Organ Pathogenicity Pathway interactions Patients Phosphatidylinositols Phosphotransferases Placebo Control Primary Neoplasm Property Randomized Regimen Regulatory T-Lymphocyte Role Skin Solid Solid Neoplasm T cell response T-Lymphocyte Subsets Testing Therapeutic Tissues Toxic effect Translating Treatment Efficacy Tumor Immunity Tumor Tissue anti-CTLA4 anti-PD1 therapy antitumor effect cancer immunotherapy cancer type cell type cellular targeting chromatin immunoprecipitation cohort draining lymph node gastrointestinal epithelium genetic approach immune checkpoint blockade immune-related adverse events immunoregulation improved in vivo inhibitor insight keratinocyte melanoma mouse model neoantigens novel pharmacologic phase II trial precursor cell programmed cell death protein 1 programs protein expression response secondary lymphoid organ selective expression single-cell RNA sequencing standard care stem survival outcome targeted treatment tertiary lymphoid organ therapy development transcription factor transcriptomics tumor tumor growth tumor microenvironment

项目摘要

Project Summary Immune checkpoint blockade (ICB) targeting CTLA-4 or PD-1 rapidly assumed its role as a standard treatment for solid tumors and can lead to dramatic, long-lasting responses; nonetheless, fewer than 30% of patients respond to monotherapy with either agent. Combination therapy results in better long-term survival outcomes, but also causes more frequent and severe immune-related adverse events (irAEs). Several novel immunotherapies are currently being explored to evaluate their anti-tumor capacity. Crucially however, most of these targets suffer from on-target, off-cell effects, as other immune cell types can express high levels of these molecules. Hence, as low overall response rates, off-cell effects and widespread immune related toxicity severely limit both treatment efficacy and monotherapy and combination therapy options, there is urgent need to develop novel immunotherapy targets that exhibit a more restricted expression profile. We have recently demonstrated that PD-1+ follicular regulatory T (TFR) cells were prevalent in tumor tissues of several cancer types in humans and mice, and that they were critical cellular determinants of anti-PD-1 treatment efficacy. TFR cells were primarily located within tertiary lymphoid structures (TLS) and exhibited superior suppressive capacity and in vivo persistence when compared to regulatory T (TREG) cells, suggesting a key role for TFR cells in impairing patient survival and impeding immunotherapy treatment efficacy. While we have shown that intratumoral TFR cells derive from TREG precursor cells, the mechanisms and transcription factors (TFs) that are driving this differentiation step are largely unknown. In Aim1, we propose to employ single-cell RNA-seq, single-cell ATAC-seq and micro- scaled ChIP assays to fully characterize the transcriptomic signatures of tumor-infiltrating TREG cells, transitioning (4-1BB+) TREG cells and TFR cells. Elucidating the enhancer profiles in different developmental stages of TREG to TFR differentiation is likely to provide crucial insights into the TFs that instruct this differentiation step. These analyses will define genes and TFs that are pivotal for the heightened suppressive capacity of TFR cells, as well as for their maintenance or differentiation. Strategies to deplete TREG cells or to curb their functionality with the aim of enhancing anti-tumor immunity are being intensively investigated. Crucially however, most of these approaches are based on antibodies (i.e., ADCC-optimized for TREG cell depletion; i.e. anti-CTLA-4), which have an inherently long half-life in vivo, thus increasing the likelihood of causing irAEs. Conversely, our data imply that alternative dosing regimens of Phosphoinositide 3-kinase δ (PI3Kδ) inhibitors might offer a pathway to target TFR cells more specifically. We propose that PI3Kδ represents a novel and appealing immunotherapy target in solid tumors. In Aim 2 and Aim 3, we will assess whether alternative dosing regimens of PI3Kd inhibitors can be utilized to effectively and safely exploit the immunomodulatory impact of PI3Kδ inhibitors in solid cancers and whether a transient depletion or inhibition of TFR cells might suffice to restrict the immunosuppressive milieu in the tumor and thus drive anti-tumor immunity without causing toxicity.

项目总结