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CDK4/6 inhibition during CD8 T cell priming potentiates memory formation in mice and humans

CD8 T 细胞启动期间的 CDK4/6 抑制可增强小鼠和人类的记忆形成

基本信息

批准号：
10382325
负责人：
Stephanie Dougan
金额：
$ 44.5万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-05 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10382325
关键词：
ATAC-seq Achievement Adjuvant Adoptive Transfer Affect Affinity Antigens Binding Binding Sites Blood Blood Cells Blood Circulation Blood specimen Breast Cancer Patient Breast Cancer Treatment CD8-Positive T-Lymphocytes CD8B1 gene CDK4 gene Cancer Patient Cell Cycle Cell Cycle Regulation Cell Lineage Cell division Cells Chromatin Clinic Clinical Clinical Trials Clinical Trials Design Co-Immunoprecipitations Communicable Diseases Cytostatics DNA Data Destinations Development Disease remission Effector Cell G1 Arrest Gene Expression Gene Expression Profile Gene Expression Profiling Gene Silencing Genes Genetic Transcription Goals Hepatitis Heterogeneity Human Immunity Immunologics Immunotherapeutic agent In Vitro Individual Link Malignant Neoplasms Mass Spectrum Analysis Memory Minority Modeling Molecular Mus Nature PD-1 blockade Paper Patients Pharmaceutical Preparations Physiological Positioning Attribute Proteins RNA RUNX3 gene Reporting Resolution Role Sampling Seminal T cell therapy T memory cell T-Lymphocyte Technology Testing Tissue Sample Tissues Toxic effect Transcription Repressor Tumor Immunity Up-Regulation blood treatment cancer immunotherapy chromatin immunoprecipitation cytokine drug action immune checkpoint blockade improved in vivo inhibitor inhibitor therapy long term memory mouse model neoplastic cell patient safety phase I trial phase II trial prevent response therapy design transcription factor tumor tumor growth

项目摘要

Project Summary Cancer immunotherapy’s signature achievement is extension of overall survival with long-term durable remissions in a minority of patients. However, the question of how memory CD8 T cells form in cancer patients is poorly understood. Our long-term goal is to understand the relationship between cell cycle regulation and CD8 T cell memory fate. We examined CDK4/6 inhibition in mouse and human CD8 T cells during T cell priming and found a dramatic skewing of CD8 T cells toward a memory fate. Antigen-specific CD8 T cells treated ex vivo with CDK4/6i displayed increased long-lived memory responses upon adoptive transfer into mice. We further used single cell transcriptional profiling to evaluate recently activated human CD8 T cells from blood of breast cancer patients pre- and on-treatment with the CDK4/6i palbociclib or abemaciclib. TCR clonotype tracking and RNA velocity analysis revealed that CDK4/6 inhibition increased the ratio of central memory to effector CD8 T cell precursors. Analysis of paired samples showed that MYC targets were downregulated by CDK4/6 inhibitor therapy in humans, consistent with an increase in the transcriptional repressor MXD4. Our central hypothesis is that CDK4/6 inhibition in CD8 T cells in both mice and humans augments long-term protective immunity. To test this, we will use state-of-the-art technologies including: 1) TRP1 transnuclear mice developed by our lab to study antigen-specific TCRs with a physiologic range of affinities for an endogenous antigen; 2) scRNAseq and TCR clonotype tracking to analyze a large bank of longitudinal blood and matched tissue samples from patients on a Phase II trial; 3) ChIPseq, and co-immunoprecipitations to determine the molecular basis linking CDK4/6 inhibition to memory cell fate in CD8 T cells. In Aim 1 we will identify the molecular mechanism linking CDK4 and/or CDK6 to induction of memory cell fate. Slowing the cell cycle using other cell cycle inhibitors or by taking advantage of natural heterogeneity in cell division rates does not potentiate memory formation in CD8 T cells, implying a unique role for CDK4 and/or CDK6 in conferring a memory cell fate. We will identify the transcriptional regulators affected by CDK4/6 inhibition, with a focus on MYC and RUNX3. Combination of CDK4/6 inhibitors with PD-1 blockade in the clinic results in unexpected treatment-limiting toxicity. In Aim 2 we propose that a short course of CDK4/6 inhibition would successfully potentiate CD8 T cell memory, thus allowing cessation of the CDK4/6 inhibitor to minimize or obviate overlap with PD-1 blockade. We will test this hypothesis in mice using our TRP1 CD8 T cell adoptive transfer model, and in humans using 29 paired blood and tissue samples from a Phase I trial of CDK4/6 inhibition with PD-1 blockade. We will use high- resolution single-cell transcriptional profiling of recently activated CD8 T cells to track individual TCR clonotypes and their transcriptional profiles in CDK4/6 inhibitor pre- and on-treatment blood and tissue samples. Impact: A basic understanding of the mechanistic role of CD4/6 in CD8 T cell fate decisions will allow for better design of clinical trials in cancer or infectious disease using CDK4/6i as adjuvants to promote CD8 T cell memory.

项目总结