The CXCR3 Chemokine System in Cancer Immunotherapy

癌症免疫治疗中的 CXCR3 趋化因子系统

基本信息

批准号：
10053710
负责人：
ANDREW D LUSTER
金额：
$ 37.62万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10053710
关键词：
Adoptive Cell Transfers Antigen-Presenting Cells Antigens Antitumor Response Behavior Blood CD8-Positive T-Lymphocytes CD8B1 gene CXC chemokine receptor 3 CXCL10 gene CXCL11 gene CXCL9 gene CXCR3 gene Cancer Patient Cell Communication Cell physiology Cells Clinical Colon Carcinoma Complex Data Disease-Free Survival Effectiveness Epigenetic Process Eragrostis Generations Heterogeneity Human Immune Immune response Immune system Immunotherapy Infiltration Inflammation Interferon Receptor Knowledge Leukocytes Ligands MC38 Malignant Neoplasms Malignant neoplasm of lung Mediating Memory Modeling Mus PD-1 blockade PET/CT scan PTEN gene Pathway interactions Patient-Focused Outcomes Patients Peripheral Phenotype Play Population Prognostic Marker Regulation Regulatory Pathway Regulatory T-Lymphocyte Reporter Resistance Role Signal Transduction Site Staging System T cell response T-Lymphocyte Testing Th1 Cells Tissues Treatment Efficacy Tumor Tissue Tumor-infiltrating immune cells Work X-Ray Computed Tomography anti-PD-1 anti-PD1 therapy anti-tumor immune response base cancer cell cancer immunotherapy cancer therapy cell killing cell motility cell type chemokine chemokine receptor density effective therapy effector T cell epigenetic silencing exhaust exhaustion fighting immune checkpoint blockade improved intravital microscopy lymph nodes melanoma mouse model neoplastic cell novel programmed cell death protein 1 recruit response response biomarker tumor tumor microenvironment

项目摘要

The recent approval of immune checkpoint blockade, such as anti-PD-1, has marked a milestone in cancer therapy. Checkpoint blockade “reinvigorates” an “exhausted” anti-tumor T cell response, which can result in a durable clinical response. However, only a fraction of patients respond to immune checkpoint blockade, and it only works in a subset of cancers. Improving the efficacy of checkpoint blockade is of paramount importance and is seemingly within reach but will require a better understanding of the molecules that control the complex interactions of immune cells in the tumor micro-environment (TME) required for effective checkpoint blockade therapy. Chemokines are chemotactic cytokines that orchestrate the migratory behavior and cellular interactions of leukocytes, and therefore have great impact upon anti-tumor immune responses. CXCR3 is a chemokine receptor for the interferon-inducible chemokines - CXCL9, CXCL10, and CXCL11- and is highly expressed on CD4+ Th1 cells and CD8+ T effector (Teff) cells. CXCR3 ligands have been correlated with the presence of Teff within tumors and disease free survival. We have exciting data that CXCR3 is required for anti-PD-1 immunotherapy. Based on the importance of CXCR3 for T cell recruitment to sites of inflammation, it is logical to predict that CXCR3 plays an important role in Teff entry into tumors following anti-PD-1 therapy. However, recent provocative preliminary data leads us to believe that CXCR3 is playing even more important roles within the tumor following anti-PD-1, and is likely critical to “jump start” the anti-tumor immune response in the TME. Recent studies have revealed heterogeneity in exhausted T cell (Tex) populations and defined Tex subsets that differ in their potential for reinvigoration by PD-1 blockade. We have found that CXCR3 expression on Teff inversely correlates with markers of exhaustion. We hypothesize that CXCR3 plays a functional role in the ability of Tex to become reinvigorated within the tumor following PD-1 blockade. In Aim 1, we will define the mechanisms by which CXCR3 contributes to the efficacy of PD-1 blockade therapy for cancer. This will include examining whether CXCR3 plays a critical role enhancing the interaction of Tex with the most relevant activated antigen-presenting cells in the tumor and facilitating the ability of Teff to locate and kill cancer cells following anti-PD-1 therapy. In Aim 2, we will determine if augmenting the CXCR3 chemokine system can improve the efficacy of anti-PD-1 therapy as well as convert anti-PD-1 nonresponsive tumors into responsive tumors. We will also determine if counter-regulatory mechanisms within the tumor, such as epigenetic silencing and CXCR3-expressing regulatory T cells, limit the effectiveness of anti-PD-1 therapy by suppressing CXCL9 and CXCL10 expression in tumors. If these pathways limit CXCR3+CD8+ T cell function in the tumor, we will devise strategies to circumvent these counter-regulatory responses. Finally, we will determine if the CXCR3 chemokine system can be used as a biomarker for response to anti-PD-1 therapy in a murine model and in patients with cancer.

最近批准的免疫检查点阻断（例如抗 PD-1）标志着癌症治疗的一个里程碑检查点封锁会“重振”“疲惫不堪”的抗肿瘤 T 细胞反应，从而导致然而，只有一小部分患者对免疫检查点阻断有反应。仅对一部分癌症有效，提高检查点封锁的功效至关重要。似乎触手可及，但需要更好地了解控制该复合物的分子有效阻断检查点所需的肿瘤微环境（TME）中免疫细胞的相互作用趋化因子是协调迁移行为和细胞的趋化细胞因子。 CXCR3 与白细胞相互作用，因此对抗肿瘤免疫反应有很大影响。干扰素诱导趋化因子 CXCL9、CXCL10 和 CXCL11 的趋化因子受体，并且高度 CD4+ Th1 细胞和 CD8+ T 效应 (Teff) 细胞上表达的 CXCR3 配体与我们有令人兴奋的数据表明肿瘤内存在 Teff 和无病生存所必需的。基于 CXCR3 对于 T 细胞募集至炎症部位的重要性，抗 PD-1 免疫疗法。可以逻辑地预测 CXCR3 在抗 PD-1 治疗后 Teff 进入肿瘤中发挥重要作用。然而，最近具有争议性的初步数据让我们相信 CXCR3 的作用更加重要抗 PD-1 后在肿瘤内的作用，并且可能对于“快速启动”抗肿瘤免疫反应至关重要最近的研究揭示了耗尽 T 细胞 (Tex) 群体的异质性并定义了 Tex。我们发现 CXCR3 的恢复潜力不同。我们发现 CXCR3 的表达与疲劳标记呈负相关。在目标 1 中，Tex 在 PD-1 阻断后在肿瘤内恢复活力的功能作用。我们将定义 CXCR3 促进 PD-1 阻断疗法疗效的机制这将包括检查 CXCR3 是否在增强 Tex 与癌症的相互作用中发挥关键作用。肿瘤中最相关的活化抗原呈递细胞，并促进 Teff 定位和定位的能力抗 PD-1 治疗后杀死癌细胞在目标 2 中，我们将确定是否增强 CXCR3 趋化因子。系统可以提高抗PD-1治疗的疗效，并将抗PD-1无反应的肿瘤转化为我们还将确定肿瘤内是否有反调节机制，例如表观遗传沉默和表达 CXCR3 的调节性 T 细胞通过以下方式限制了抗 PD-1 治疗的有效性抑制肿瘤中 CXCL9 和 CXCL10 的表达，如果这些途径限制了 CXCR3+CD8+ T 细胞的功能。最后，我们将制定策略来规避这些反监管反应。确定 CXCR3 趋化因子系统是否可以用作抗 PD-1 治疗反应的生物标志物小鼠模型和癌症患者。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

During Aspergillus Infection, Monocyte-Derived DCs, Neutrophils, and Plasmacytoid DCs Enhance Innate Immune Defense through CXCR3-Dependent Crosstalk.

在曲霉菌感染期间，单核细胞衍生的 DC、中性粒细胞和浆细胞样 DC 通过 CXCR3 依赖性串扰增强先天免疫防御。

DOI：
发表时间：
2020-07-08
期刊：
影响因子：
30.3
作者：
Guo, Yahui;Kasahara, Shinji;Jhingran, Anupam;Tosini, Nicholas L;Zhai, Bing;Aufiero, Mariano A;Mills, Kathleen A M;Gjonbalaj, Mergim;Espinosa, Vanessa;Rivera, Amariliz;Luster, Andrew D;Hohl, Tobias M
通讯作者：
Hohl, Tobias M

Antihistamines for cancer immunotherapy: More than just treating allergies.

用于癌症免疫治疗的抗组胺药：不仅仅是治疗过敏。