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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，如抗pd -1，标志着癌症的一个里程碑