Enhancing TIL populations and immunotherapy efficacy in melanoma by modulating fucosylation

通过调节岩藻糖基化增强黑色素瘤的 TIL 群体和免疫治疗功效

基本信息

批准号：
10406254
负责人：
Eric Kirk Lau
金额：
$ 38.56万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10406254
关键词：
Address Adoptive Cell Transfers Affect Antigen Presentation Antigens Biological CD4 Positive T Lymphocytes CD8B1 gene Cell physiology Cell surface Cells Cellular biology Clinical Coculture Techniques Data Development Diagnosis Dietary Sugars Effectiveness Fucose Goals HLA-DRB1 Human IL2RA gene Immune Immune system Immunotherapy In Vitro Infiltration Laboratories Lymphocyte Count MHC Class II Genes Malignant Neoplasms Mediating Melanoma Cell Memory Modality Modeling Mus Nature Neoplasm Metastasis Outcome Patients Phenotype Plants Population Post-Translational Protein Processing Process Proteins Proteomics Reporting Resistance Role Signal Transduction Skin Cancer Specimen Stains T-Cell Activation T-Lymphocyte Testing Therapeutic Therapeutic Agents Time Training Tumor Immunity Tumor Suppression Tumor-Infiltrating Lymphocytes Tumor-infiltrating immune cells anti-PD-1 anti-melanoma immunity antitumor effect base cytokine cytotoxic feeding immune checkpoint blockade immune function immunogenicity improved innovation insight melanoma multidisciplinary novel therapeutics patient prognosis patient response patient stratification predict responsiveness prognostic value recruit response side effect sugar therapy resistant trafficking translational approach treatment strategy tumor tumor growth tumor infiltrating lymphocyte therapy

项目摘要

PROJECT SUMMARY/ABSTRACT Our immune system is crucial for recognizing and suppressing cancers in the body. Unfortunately, melanomas, one of the most lethal skin cancers, can interact with and inactivate immune cells. Among the most effective anti-melanoma therapies are immunotherapies that reactivate or “train” the anti-tumor activities of immune cells. However, the effectiveness of immunotherapies is currently limited to ~30% of patients. Although the underlying causes are unclear, lack of responsiveness in patients is associated with insufficient infiltration of tumors by immune cells. Thus, studies aimed at elucidating melanoma:immune interactions and increasing the immune infiltration of tumors are required to improve immunotherapies. We discovered a potential way to increase the efficacy of immunotherapies by boosting infiltration of melanomas with tumor-suppressing immune cells using the plant sugar L-fucose. In a process called fucosylation, cells used L-fucose to modify proteins, affecting their maturation/function. We found that fucosylation is generally reduced during melanoma progression in humans, prompting us to test if increasing L- fucose/fucosylation levels in melanomas elicits therapeutically beneficial effects. Simply feeding L-fucose to melanoma-bearing mice reduces tumor growth and metastasis by >50% (Lau et al. Sci Signal 2015). Intriguingly, those smaller tumors contain 10-50 times more tumor-infiltrating lymphocytes (“TIL”) than tumors from mice not fed L-fucose. Genetically increasing the fucosylation of melanoma cells elicits the same effects, suggesting that melanoma fucosylation triggers anti-tumor immunity. We determined that CD4+/CD25- T cells are crucial for L-fucose-triggered recruitment of TILs including CD8+ T, NK, and DCs that suppress tumor growth. We identified the immune-regulating protein HLA-DRB1 as fucosylated, and its expression is crucial for TIL recruitment/tumor suppression, prompting our hypothesis that fucosylation of HLA-DRB1 triggers CD4+/CD25- T cell-mediated TIL recruitment and suppression of melanoma. However, how fucosylation regulates HLA-DRB1 to mediate anti-melanoma immunity, if those effects are due to increased tumor immunogenicity, CD4+/CD25- T cell function, or both, and if L-fucose/fucosylation can enhance immunotherapy efficacy or have prognostic utility is not known. We propose 3 Specific Aims (SAs) to test our hypothesis and address these questions: ·SA1: Determine how fucosylation regulates the localization and immune function of HLA-DRB1 ·SA2: Determine how systemic fucosylation affects CD4+/CD25- T cell biology. ·SA3: Determine if L-fucose/fucosylation enhances anti-PD1/TIL therapy and predicts patient prognosis Our goal is to provide key biological/mechanistic insights into melanoma:immune interactions, which will establish a basis for developing enhanced, fucosylation-based patient stratification and treatment strategies.

项目摘要/摘要我们的免疫系统对于识别和抑制体内的癌症至关重要。不幸的是，黑色素瘤，最致命的皮肤癌之一可以与免疫细胞相互作用并失活。最有效的抗黑色素瘤疗法是免疫疗法，可重新激活或“训练”免疫的抗肿瘤活性细胞。但是，免疫疗法的有效性目前仅限于约30％的患者。虽然根本原因尚不清楚，患者缺乏反应性与渗透不足有关免疫细胞的肿瘤。那是旨在阐明黑色素瘤的研究：免疫相互作用并增加需要肿瘤的免疫浸润以改善免疫疗法。我们发现了一种潜在的方法来提高免疫疗法的效率黑色素瘤与肿瘤抑制免疫细胞使用植物糖l-凝糖。在一个称为的过程中岩藻糖基化，细胞使用L-柠檬糖修饰蛋白质，影响其成熟/功能。我们发现在人类黑色素瘤进展过程中，岩藻糖基化通常会降低，促使我们测试是否增加L- 黑色素瘤中的岩藻糖/岩藻糖基化水平会引起热有益作用。简单地喂l-浓汤含有黑色素瘤的小鼠将肿瘤的生长和转移降低> 50％（Lau等人SCI Signal 2015）。有趣的是，这些较小的肿瘤含有肿瘤浸润淋巴细胞（“ TIL”）的10-50倍来自未喂l-饮食的小鼠。从遗传上增加黑色素瘤细胞的岩藻糖基化引起相同的作用，提示黑色素瘤化葡萄糖基化会触发抗肿瘤免疫力。我们确定CD4+/CD25-T细胞对于抑制肿瘤的CD8+ T，NK和DC，包括CD8+ T，NK和DC在内的L-凝血触发的募集至关重要生长。我们将免疫调节的蛋白HLA-DRB1鉴定为诱导性，其表达对于 TIL募集/肿瘤抑制，促使我们的假设是HLA-DRB1触发器的岩藻糖基化 CD4+/CD25- T细胞介导的TIL募集和黑色素瘤的抑制。但是，如何构造化如果这些作用是由于肿瘤的增加，则调节HLA-DRB1介导抗黑色素瘤免疫学免疫原性，CD4+/CD25- T细胞功能，或两者兼而有之，如果L-戊糖/烟糖基化可以增强免疫疗法疗效或具有预后效用尚不清楚。我们提出了3个特定目标（SAS）来检验我们的假设和解决以下问题： SA1：确定岩藻糖基化如何调节HLA-DRB1的定位和免疫功能 ·SA2：确定系统性岩藻糖基化如何影响CD4+/CD25-T细胞生物学。 SA3：确定L-戊糖/岩藻糖基化是否增强了抗PD1/TIL治疗并预测患者提示我们的目标是为黑色素瘤提供关键的生物/机械见解：免疫相互作用，这将建立开发增强的基于诱导的患者分层和治疗策略的基础。