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.

项目概要/摘要不幸的是，我们的免疫系统对于识别和抑制体内的癌症至关重要。最致命的皮肤癌之一，可以与免疫细胞相互作用并使免疫细胞失活。抗黑色素瘤疗法是重新激活或“训练”免疫细胞的抗肿瘤活性的免疫疗法。然而，免疫疗法的有效性目前仅限于约 30% 的患者。根本原因尚不清楚，患者缺乏反应性与浸润不足有关因此，研究旨在阐明黑色素瘤：免疫相互作用并增加免疫细胞对肿瘤的影响。肿瘤的免疫浸润需要改善免疫治疗。我们发现了一种通过促进细胞浸润来提高免疫疗法疗效的潜在方法使用植物糖 L-岩藻糖抑制黑色素瘤的免疫细胞。岩藻糖基化，细胞使用 L-岩藻糖修饰蛋白质，影响其成熟/功能。在人类黑色素瘤进展过程中，岩藻糖基化通常会减少，这促使我们测试是否增加 L- 黑色素瘤中的岩藻糖/岩藻糖基化水平只需添加 L-岩藻糖即可产生有益的治疗效果。携带黑色素瘤的小鼠肿瘤生长和转移减少>50%（Lau et al. Sci Signal 2015）。有趣的是，这些较小的肿瘤含有比肿瘤多 10-50 倍的肿瘤浸润淋巴细胞 (“TIL”) 来自未喂食L-岩藻糖的小鼠的基因增加黑色素瘤细胞的岩藻糖基化会引起相同的效果，表明黑色素瘤岩藻糖基化会触发抗肿瘤免疫。我们确定 CD4+/CD25- T 细胞。对于 L-岩藻糖触发的 TIL 募集至关重要，包括抑制肿瘤的 CD8+ T、NK 和 DC 我们发现免疫调节蛋白 HLA-DRB1 是岩藻糖基化的，它的表达对于生长至关重要。 TIL 募集/肿瘤抑制，促使我们假设 HLA-DRB1 的岩藻糖基化会触发 CD4+/CD25- T 细胞介导的 TIL 募集和抑制黑色素瘤然而，岩藻糖基化是如何进行的。调节 HLA-DRB1 以介导抗黑色素瘤免疫（如果这些影响是由于肿瘤增加所致）免疫原性、CD4+/CD25- T 细胞功能或两者兼而有之，以及 L-岩藻糖/岩藻糖基化是否可以增强免疫治疗疗效或预后效用尚不清楚，我们提出了 3 个具体目标 (SA) 来检验我们的假设和结果。解决这些问题： ·SA1：确定岩藻糖基化如何调节HLA-DRB1的定位和免疫功能 ·SA2：确定全身岩藻糖基化如何影响 CD4+/CD25- T 细胞生物学。 ·SA3：确定L-岩藻糖/岩藻糖基化是否增强抗PD1/TIL治疗并预测患者预后我们的目标是提供关于黑色素瘤的关键生物学/机制见解：免疫相互作用，这将为开发增强的、基于岩藻糖基化的患者分层和治疗策略奠定基础。