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HLA-DRB1的聚焦调节CD4+ T细胞介导的抗黑色素瘤免疫，提高免疫治疗效果

原文发布日期：2023-01-23

英文摘要：

摘要翻译：

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文章：

HLA-DRB1的聚焦调节CD4+ T细胞介导的抗黑色素瘤免疫，提高免疫治疗效果

Fucosylation of HLA-DRB1 regulates CD4+ T cell-mediated anti-melanoma immunity and enhances immunotherapy efficacy

原文发布日期：2023-01-23

英文摘要：

Immunotherapy efficacy is limited in melanoma, and combinations of immunotherapies with other modalities have yielded limited improvements but also adverse events requiring cessation of treatment. In addition to ineffective patient stratification, efficacy is impaired by paucity of intratumoral immune cells (itICs); thus, effective strategies to safely increase itICs are needed. We report that dietary administration of l-fucose induces fucosylation and cell surface enrichment of the major histocompatibility complex (MHC)-II protein HLA-DRB1 in melanoma cells, triggering CD4+ T cell-mediated increases in itICs and anti-tumor immunity, enhancing immune checkpoint blockade responses. Melanoma fucosylation and fucosylated HLA-DRB1 associate with intratumoral T cell abundance and anti-programmed cell death protein 1 (PD1) responder status in patient melanoma specimens, suggesting the potential use of melanoma fucosylation as a strategy for stratifying patients for immunotherapies. Our findings demonstrate that fucosylation is a key mediator of anti-tumor immunity and, importantly, suggest that l-fucose is a powerful agent for safely increasing itICs and immunotherapy efficacy in melanoma.

摘要翻译：

黑色素瘤的免疫疗法效果有限，在某些情况下结合其他手段可取得一定程度的改善，但同时也伴随着不良事件导致治疗终止。除了无效的患者分层标准外，由于肿瘤内部缺乏足够的免疫细胞(itICs)，免疫功能也无法正常发挥，因此如何安全有效增加itICs成为重要策略。我们发现，膳食补充半乳糖苷（l-fucose）诱导黑色素瘤细胞表面富集表达主要组织相容性复合物Ⅱ类（MHC-II）上的HLA-DRB1蛋白，从而激活CD4+ T细胞，导致肿瘤内部itICs和抗肿瘤免疫反应数量增加，并且改善了针对黑色素瘤患者的免疫检查点阻断治疗效果。此外，在患者黑色素瘤标本中发现，黑素瘤半乳糖苷化以及与之结合的HLA-DRB1蛋白常与肿瘤内T细胞丰富程度和抗程序 cell death protein 1 (PD1)应答状态相关联，这表明可以将黑色素瘤半乳糖苷化作为筛选患者免疫疗法适应症的策略。我们的研究发现，半乳糖苷化是抗肿瘤免疫的重要调节因子，更重要的是，提示使用半乳糖苷作为安全有效增加itICs和提高黑色素瘤免疫治疗效果的关键因素。