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.

免疫切克点封锁（例如抗PD-1）的最新批准标志着癌症的里程碑治疗。检查点封锁“重振”了“耗尽”的抗肿瘤T细胞响应，这可能导致耐用的临床反应。但是，只有一小部分患者对免疫检查点封锁做出反应，并且仅在癌症的子集中起作用。提高检查站封锁的效率至关重要并且似乎已触及，但需要更好地理解控制复合物的分子有效检查点阻断所需的肿瘤微环境（TME）中免疫细胞的相互作用治疗。趋化因子是趋化的细胞因子，可协调迁移行为和细胞白细胞的相互作用，因此对抗肿瘤免疫调查有很大影响。 CXCR3是a 干扰素诱导趋化因子-CXCL9，CXCL10和CXCL11-的趋化因子受体 - 高度在CD4+ Th1细胞和CD8+ T效应子（TEFF）细胞上表达。 CXCR3配体与在肿瘤中存在TEFF和无疾病生存。我们有令人兴奋的数据，即CXCR3需要抗PD-1免疫疗法。基于CXCR3对T细胞募集到炎症部位的重要性，IT 逻辑上可以预测CXCR3在抗PD-1治疗后TEFF进入肿瘤中起重要作用。但是，最近的挑衅性初步数据使我们相信CXCR3在发挥更重要的作用抗PD-1之后肿瘤内的角色，对于“开始”抗肿瘤免疫反应可能至关重要在TME中。最近的研究表明，耗尽的T细胞（TEX）种群的异质性并定义了Tex 在PD-1阻断中重现的潜力不同的子集。我们发现CXCR3 TEFF上的表达与疲惫的标记成反比。我们假设CXCR3扮演 PD-1阻滞后，在肿瘤中恢复活力的Tex能力中的功能作用。在AIM 1中，我们将定义CXCR3有助于PD-1阻断疗法的效率的机制癌症。这将包括检查CXCR3是否起着至关重要的作用肿瘤中最相关的激活抗原呈递细胞，并支持TEFF定位和抗PD-1治疗后杀死癌细胞。在AIM 2中，我们将确定是否增加CXCR3趋化因子系统可以提高抗PD-1治疗的效率，并将抗PD-1无反应性肿瘤转化为反应性肿瘤。我们还将确定肿瘤内的反调节机制是否表观遗传沉默和表达CXCR3的调节T细胞，限制了抗PD-1治疗的有效性抑制肿瘤中的CXCL9和CXCL10表达。如果这些途径限制了CXCR3+ CD8+ T细胞功能肿瘤，我们将制定策略来规避这些反调节性反应。最后，我们会的确定CXCR3趋化因子系统是否可以用作对抗PD-1治疗的生物标志物鼠模型和癌症患者。