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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.

项目总结/文摘