免疫检查点阻断通过扩增效应 CD8⁺ T 细胞克隆增强淋巴细胞清除性化疗诱导的抗肿瘤免疫
Immune Checkpoint Blockade Augments Lymphodepleting Chemotherapy-Induced Antitumor Immunity by Expanding Effector CD8+ T-cell Clones.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题:Acral Melanoma Is Infiltrated with cDC1s and Functional Exhausted CD8 T Cells Similar to the Cutaneous Melanoma of Sun-Exposed Skin.
Acral Melanoma Is Infiltrated with cDC1s and Functional Exhausted CD8 T Cells Similar to the Cutaneous Melanoma of Sun-Exposed Skin.
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肢端黑色素瘤(AM)是非高加索人群中最常见的黑色素瘤,但目前对其研究仍严重不足。由于AM缺乏其他皮肤黑色素瘤所具有的紫外线辐射突变特征,它被认为缺乏免疫原性,并且很少被纳入旨在恢复免疫细胞抗肿瘤功能的新型免疫治疗方案的临床试验中。
我们研究了墨西哥社会保障研究所(IMSS)的墨西哥黑色素瘤患者队列(n = 38),发现AM占比过高(73.9%)。我们开发了一种多参数免疫荧光技术,结合机器学习图像分析,以评估黑色素瘤间质中经典1型树突状细胞(cDC1)和CD8 T细胞的存在情况,这两种细胞是对抗肿瘤反应最相关的免疫细胞类型。
我们观察到,这两种细胞类型在AM中的浸润水平与其他皮肤黑色素瘤相似甚至更高。两种黑色素瘤类型均存在程序性细胞死亡蛋白1(PD-1+)CD8 T细胞和PD-1配体(PD-L1+)cDC1。尽管如此,CD8 T细胞似乎保留了其效应功能和扩增能力,因为它们表达干扰素-γ(IFN-γ)和KI-67。在晚期III期和IV期黑色素瘤中,cDC1和CD8 T细胞的密度显著降低,支持这些细胞控制肿瘤进展的能力。这些数据还表明,AM可能对anti-PD-1-PD-L1免疫治疗有反应。
Acral melanoma (AM) is the most common melanoma in non-Caucasian populations, yet it remains largely understudied. As AM lacks the UV-radiation mutational signatures that characterize other cutaneous melanomas, it is considered devoid of immunogenicity and is rarely included in clinical trials assessing novel immunotherapeutic regimes aiming to recover the antitumor function of immune cells.
We studied a Mexican cohort of melanoma patients from the Mexican Institute of Social Security (IMSS) (n = 38) and found an overrepresentation of AM (73. 9%).
We developed a multiparametric immunofluorescence technique coupled with a machine learning image analysis to evaluate the presence of conventional type 1 dendritic cells (cDC1) and CD8 T cells in the stroma of melanoma, two of the most relevant immune cell types for antitumor responses.
We observed that both cell types infiltrate AM at similar and even higher levels than other cutaneous melanomas. Both melanoma types harbored programmed cell death protein 1 (PD-1 + ) CD8 T cells and PD-1 ligand (PD-L1 + ) cDC1s. Despite this, CD8 T cells appeared to preserve their effector function and expanding capacity as they expressed interferon-γ (IFN-γ) and KI-67.
The density of cDC1s and CD8 T cells significantly decreased in advanced stage III and IV melanomas, supporting these cells' capacity to control tumor progression. These data also argue that AM could respond to anti-PD-1-PD-L1 immunotherapy.
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