肿瘤细胞治疗研究
英文原题：HLA export by melanoma cells decoys cytotoxic T cells to promote immune evasion.
这些发现表明，MHC输出保护黑色素瘤免受T细胞的细胞毒性作用。
尽管黑色素瘤细胞通常表达高负荷的突变蛋白，但反应性 T 细胞的浸润很少能产生根除肿瘤的免疫。我们发现，黑色素瘤细胞分泌的大型细胞外囊泡，即黑素体，装饰有主要组织相容性复合体（MHC）分子，这些分子通过其 T 细胞受体（TCR）刺激 CD8+ T 细胞，导致 T 细胞功能障碍和凋亡。免疫肽组学和 T 细胞受体测序（TCR-seq）分析显示，这些黑素体携带与 MHC 结合的肿瘤相关抗原，具有更高的亲和力和免疫原性，它们与起源肿瘤细胞竞争直接的 TCR-MHC 相互作用。对黑色素瘤患者活检的分析证实，黑素体捕获浸润的淋巴细胞，诱导部分激活，并降低 CD8+ T 细胞的细胞毒性。在体内抑制黑素体分泌显著减少了肿瘤免疫逃逸。这些发现表明，MHC 输出保护黑色素瘤免受 T 细胞的细胞毒性作用。我们的研究强调了一种新的免疫逃逸机制，并提出了一种增强肿瘤免疫的治疗途径。
While melanoma cells often express a high burden of mutated proteins, the infiltration of reactive T cells rarely results in tumor-eradicating immunity. We discovered that large extracellular vesicles, known as melanosomes, secreted by melanoma cells are decorated with major histocompatibility complex (MHC) molecules that stimulate CD8 + T cells through their T cell receptor (TCR), causing T cell dysfunction and apoptosis. Immunopeptidomic and T cell receptor sequencing (TCR-seq) analyses revealed that these melanosomes carry MHC-bound tumor-associated antigens with higher affinity and immunogenicity, which compete with their tumor cell of origin for direct TCR-MHC interactions. Analysis of biopsies from melanoma patients confirmed that melanosomes trap infiltrating lymphocytes, induce partial activation, and decrease CD8 + T cell cytotoxicity. Inhibition of melanosome secretion in vivo significantly reduced tumor immune evasion. These findings suggest that MHC export protects melanoma from the cytotoxic effects of T cells. Our study highlights a novel immune evasion mechanism and proposes a therapeutic avenue to enhance tumor immunity.
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