The CXCR3 Chemokine System in Cancer Immunotherapy

癌症免疫治疗中的 CXCR3 趋化因子系统

• 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
• 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

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剂，如抗PD-1，标志着癌症的里程碑 疗法检查点阻断“重振”“耗尽的”抗肿瘤T细胞应答，这可能导致免疫应答。 持久的临床反应。然而，只有一小部分患者对免疫检查点阻断有反应， 只对一部分癌症有效提高检查站封锁的效力至关重要 这似乎触手可及，但需要更好地了解控制复合物的分子 肿瘤微环境（TME）中免疫细胞的相互作用是有效检查点阻断所需的 疗法趋化因子是一种趋化性细胞因子，它协调细胞的迁移行为和细胞的增殖。 白细胞的相互作用，因此对抗肿瘤免疫应答有很大影响。CXCR 3是一种 趋化因子受体的干扰素诱导趋化因子-CXCL 9，CXCL 10，和CXCL 11-和高度 在CD 4 + Th 1细胞和CD 8 + T效应细胞（Teff）上表达。CXCR 3配体与 Teff在肿瘤内的存在和无病存活。我们有令人兴奋的数据，CXCR 3是必需的， 抗PD-1免疫疗法基于CXCR 3对于T细胞募集到炎症部位的重要性， 符合逻辑地预测CXCR 3在抗PD-1治疗后Teff进入肿瘤中起重要作用。 然而，最近的挑衅性初步数据使我们相信，CXCR 3发挥着更重要的作用， 在抗PD-1后在肿瘤内发挥作用，并且可能对“跳跃启动”抗肿瘤免疫应答至关重要。 在TME。最近的研究揭示了耗尽的T细胞（Tex）群体的异质性，并定义了Tex 这些亚群在通过PD-1阻断而恢复活力的潜力方面不同。我们发现CXCR 3 Teff的表达与衰竭标志物负相关。我们假设CXCR 3发挥着 在PD-1阻断后，Tex在肿瘤内恢复活力的能力中发挥功能作用。在目标1中， 我们将明确CXCR 3对PD-1阻断治疗的疗效的作用机制， 癌这将包括检查CXCR 3是否在增强Tex与 肿瘤中最相关的活化抗原呈递细胞，并促进Teff定位和 在抗PD-1治疗后杀死癌细胞。在目标2中，我们将确定是否增加CXCR 3趋化因子 系统可以提高抗PD-1治疗的功效，并将抗PD-1无反应的肿瘤转化为抗PD-1抗体。 反应性肿瘤我们还将确定肿瘤内的反调节机制，如 表观遗传沉默和表达CXCR 3的调节性T细胞，限制了抗PD-1治疗的有效性， 抑制肿瘤中CXCL 9和CXCL 10的表达。如果这些途径限制CXCR 3 + CD 8 + T细胞功能， 我们将设计策略来规避这些反调节反应。最后我们将 确定CXCR 3趋化因子系统是否可以用作在免疫治疗中对抗PD-1疗法的应答的生物标志物。 小鼠模型和癌症患者。