CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：TGF-β-mediated silencing of genomic organizer SATB1 promotes Tfh cell differentiation and formation of intra-tumoral tertiary lymphoid structures.
TGF-β-mediated silencing of genomic organizer SATB1 promotes Tfh cell differentiation and formation of intra-tumoral tertiary lymphoid structures.
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T 滤泡辅助（Tfh）细胞上的免疫检查点受体 PD-1 促进 Tfh:B 细胞相互作用及在组织内的适当定位。在此，我们研究了基因组组织者 SATB1 对 PD-1 表达的调控对 Tfh 细胞分化的影响。CD4 Cre Satb1 f/f 小鼠接种疫苗后抗原特异性 Tfh 细胞富集，而 TGF-β 介导的 SATB1 抑制增强了人 T 细胞的 Tfh 分化。
机制上，Satb1 -/- CD4 + T 细胞中高表达的 Icos 通过阻止 T 滤泡调节性细胞偏移促进 Tfh 细胞分化，并导致体内同种型转换 B 细胞反应增加。CD4 Cre Satb1 f/f 小鼠的卵巢肿瘤中积聚了肿瘤抗原特异性 LIGHT + CXCL13 + IL-21 + Tfh 细胞和三级淋巴结构（TLS）。TLS 形成以 CD4 + T 细胞和 CXCL13 依赖的方式降低肿瘤生长。转移 Tfh 细胞而非初始 CD4 + T 细胞可在肿瘤床诱导 TLS 并降低肿瘤生长。
因此，TGF-β 介导的 Satb1 沉默许可 Tfh 细胞分化，为肿瘤内 TLS 的发生提供了见解。
The immune checkpoint receptor PD-1 on T follicular helper (Tfh) cells promotes Tfh:B cell interactions and appropriate positioning within tissues.
Here, we examined the impact of regulation of PD-1 expression by the genomic organizer SATB1 on Tfh cell differentiation. Vaccination of CD4 Cre Satb1 f/f mice enriched for antigen-specific Tfh cells, and TGF-β-mediated repression of SATB1 enhanced Tfh differentiation of human T cells.
Mechanistically, high Icos expression in Satb1 -/- CD4 + T cells promoted Tfh cell differentiation by preventing T follicular regulatory cell skewing and resulted in increased isotype-switched B cell responses in vivo.
Ovarian tumors in CD4 Cre Satb1 f/f mice accumulated tumor antigen-specific, LIGHT + CXCL13 + IL-21 + Tfh cells and tertiary lymphoid structures (TLS). TLS formation decreased tumor growth in a CD4 + T cell and CXCL13-dependent manner. The transfer of Tfh cells, but not naive CD4 + T cells, induced TLS at tumor beds and decreased tumor growth.
Thus, TGF-β-mediated silencing of Satb1 licenses Tfh cell differentiation, providing insight into the genesis of TLS within tumors.
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