Antigen-Presenting Cell Control of CD8+ T Cell Exhaustion in Cancer

癌症中 CD8 T 细胞耗竭的抗原呈递细胞控制

基本信息

批准号：
10659843
负责人：
Ming Li
金额：
$ 54.23万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
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：
2023-05-01 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10659843
关键词：
Ablation Antigen Presentation Antigen-Presenting Cells Antigens Attenuated Bioenergetics CD8-Positive T-Lymphocytes Cancer Model Cancer Patient Cell Compartmentation Cell Differentiation process Cell Lineage Cell Size Cell Therapy Cell physiology Cells Cellular Immunity Characteristics Chromatin Chronic Complex Cross Presentation Cytokine Activation Cytotoxic T-Lymphocytes Dendritic Cells Development Dual-role transvestism Enhancers Exhibits FRAP1 gene Functional disorder Gene Expression Gene Expression Profile Gene Mutation Generations Genes Genetic Genetic Enhancer Element Genetic Models Globulins Growth Factor Human IFN consensus sequence binding protein Immunologic Surveillance Interferon Type II Interferons Interleukin-15 Macrophage Major Histocompatibility Complex Malignant Neoplasms Mediating Metabolic Metabolic Activation Mononuclear Mouse Strains Mus Nutrient Oxygen Phagocytes Pharmacotherapy Population Process Proteins Regulation Role Sampling Signal Transduction Specific qualifier value System T-Cell Activation T-Lymphocyte Testing Therapeutic Intervention Transforming Growth Factor beta Transforming Growth Factors Transgenic Model Tumor Promotion Tumor Tissue Tumor-associated macrophages anti-PD-1 cancer cell cancer immunotherapy cancer type cell growth cell transformation exhaust exhaustion experimental study genetic signature immune checkpoint blockade in vivo inhibitor insight loss of function lymphoid organ malignant breast neoplasm mouse model neoantigens notch protein novel overexpression progenitor programmed cell death protein 1 programs receptor recruit response targeted treatment transcription factor transcriptome tumor tumor growth tumor microenvironment

项目摘要

Project Summary Tumor-reactive cytotoxic T lymphocytes (CTLs) often progress to dysfunction defined as T cell exhaustion. Marked by expression of the programmed cell death protein 1 (PD-1), the exhausted T (Tex) cell lineage is a developmental continuum wherein PD-1low Tex progenitors give rise to terminally dysfunctional PD-1high Tex cells. Notably, the immune checkpoint blockade therapy revives Tex progenitors, but not terminal Tex cells, calling for exploration of their differentiation mechanisms and means of therapeutic intervention. In a murine cancer model, tumor development induces differentiation of tumor-associated macrophages (TAMs) in association with generation of Tex cells. Transcriptome analysis revealed that TAMs exhibit shared characteristics with type 1 dendritic cells (DC1s) including expression of the transcription factor interferon regulatory factor-8 (IRF8). IRF8 promotes TAM presentation of cancer cell antigens to CD8+ T cells similar to DC1, but TAMs differ from DC1s in promoting high PD-1 expression. Importantly, macrophage-specific deletion of IRF8 attenuates Tex cell differentiation, and suppresses tumor growth. Furthermore, human TAMs express IRF8, and a TAM IRF8 gene signature tracks with a Tex cell gene signature in multiple cancer types. Based on these findings, we hypothesize that terminal Tex cell differentiation is driven by IRF8-expressing TAMs with a tolerogenic antigen-presenting cell (APC) function in the tumor tissue, and such a TAM-Tex cell regulation axis can be targeted for novel cancer immunotherapy. To test this hypothesis, we will first determine how IRF8 is induced in TAMs, and how it promotes TAM APC function. By performing chromatin profiling experiments and using genetic mouse models, we will assess whether the TAM-enriched transcription factor Batf2 enables IRF8 autoactivation via the +32kb Irf8 enhancer element. IRF8-deficient TAMs are defective in acquiring cancer cell antigens. Using mouse strains with macrophage- or cancer cell-specific deletion of the B2m gene, we will investigate whether IRF8 promotes TAM acquisition of antigens through cross-presentation or cross-dressing. Secondly, we will define how the tolerogenic function of TAMs is specified, and how it can be reprogrammed for therapy. Compared to DC1s, TAMs express lower levels of interleukin-15 (IL-15), but exhibit heightened transforming growth factor-b (TGF-b) signaling. By generating macrophage-specific gain- or loss-of-function mouse models, we will explore whether blockage of TGF-b signaling reverses the tolerogenic APC function of TAMs in an IL-15-dependent manner, and whether overexpression of IL-15 in macrophages is sufficient to induce T cell-stimulatory TAMs in genetic models and in a cell therapy setting. Compared to DC1s, TAMs have a smaller cell size. We will investigate whether and how activation of the metabolic regulator mammalian target of rapamycin complex 1 (mTORC1) reprogram TAMs to be immunostimulatory APCs. Successful completion of this project will not only generate mechanistic insights into APC control of Tex cell differentiation in cancer, but also guide the targeting of the TAM-Tex cell regulation axis for therapy of a wide range of malignancies.

项目摘要肿瘤反应性细胞毒性T淋巴细胞（CTL）通常会发展为定义为T细胞耗尽的功能障碍。以编程细胞死亡蛋白1（PD-1）的表达为标志，耗尽的T（Tex）细胞谱系是一个发育连续性，其中PD-1LOW TEX祖细胞导致终极功能失调的PD-1高Tex 细胞。值得一提呼吁探索其分化机制和治疗干预手段。在村里癌症模型，肿瘤发展诱导肿瘤相关巨噬细胞（TAM）的分化与Tex细胞的产生相关。转录组分析表明，TAMS表现出共享 1型树突状细胞（DC1）的特征，包括转录因子干扰素的表达调节因子8（IRF8）。 IRF8促进了癌细胞抗原对CD8+ T细胞的TAM呈现类似 DC1，但TAM与DC1在促进高PD-1表达方面有所不同。重要的是，巨噬细胞特定的缺失 IRF8的含量会减弱Tex细胞的分化，并抑制肿瘤的生长。此外，人类TAMS Express IRF8和具有多种癌症类型的Tex细胞基因特征的TAM IRF8基因签名轨道。基于这些发现，我们假设末端Tex细胞分化是由表达IRF8的TAM驱动的肿瘤组织中的耐受性抗原呈递细胞（APC）功能，这种TAM-Tex细胞调节轴可以针对新型的癌症免疫疗法。为了检验这一假设，我们将首先确定IRF8是如何的在TAM中诱导及其如何促进TAM APC功能。通过执行染色质分析实验和使用遗传小鼠模型，我们将评估富含TAM的转录因子BATF2是否可以启用IRF8 通过 +32KB IRF8增强子元素进行自动活化。 IRF8缺乏的TAM在获取癌细胞方面有缺陷抗原。使用B2M基因的巨噬细胞或癌细胞特异性缺失的小鼠菌株，我们将研究IRF8是通过交叉呈递还是交叉染色来促进抗原的TAM获取。其次，我们将定义如何指定TAM的耐受功能，以及如何重新编程用于治疗。与DC1相比，TAMS表达白介素15（IL-15）的水平较低，但表现出了增强转化生长因子-B（TGF-B）信号传导。通过产生巨噬细胞特异性或功能丧失鼠标模型，我们将探索TGF-B信号的阻塞是否会逆转以IL-15依赖性方式TAM，以及巨噬细胞中IL-15的过表达是否足以使在遗传模型和细胞治疗环境中诱导T细胞刺激性TAM。与DC1相比，TAM具有一个较小的单元大小。我们将研究代谢调节剂哺乳动物靶标的激活以及如何激活雷帕霉素复合物1（MTORC1）重编程为免疫刺激性APC。成功完成这个项目不仅会产生对癌症中Tex细胞分化的APC控制的机械见解，但也指导TAM-Tex细胞调节轴的靶向，以治疗多种恶性肿瘤。