常规的 I 型树突状细胞在肿瘤引流淋巴结中维持着增殖性肿瘤抗原特异性 TCF-1 CD8 T 细胞的储备库。
Conventional type I dendritic cells maintain a reservoir of proliferative tumor-antigen specific TCF-1 CD8 T cells in tumor-draining lymph nodes.
机构信息
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA.
Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA.
出版信息
Immunity. 2021 Oct 12;54(10):2338-2353.e6. doi: 10.1016/j.immuni.2021.08.026. Epub 2021 Sep 16.
In tumors, a subset of CD8 T cells expressing the transcription factor TCF-1 drives the response to immune checkpoint blockade. We examined the mechanisms that maintain these cells in an autochthonous model of lung adenocarcinoma. Longitudinal sampling and single-cell sequencing of tumor-antigen specific TCF-1 CD8 T cells revealed that while intratumoral TCF-1 CD8 T cells acquired dysfunctional features and decreased in number as tumors progressed, TCF-1 CD8 T cell frequency in the tumor draining LN (dLN) remained stable. Two discrete intratumoral TCF-1 CD8 T cell subsets developed over time-a proliferative SlamF6 subset and a non-cycling SlamF6 subset. Blocking dLN egress decreased the frequency of intratumoral SlamF6 TCF-1 CD8 T cells. Conventional type I dendritic cell (cDC1) in dLN decreased in number with tumor progression, and Flt3L+anti-CD40 treatment recovered SlamF6 T cell frequencies and decreased tumor burden. Thus, cDC1s in tumor dLN maintain a reservoir of TCF-1 CD8 T cells and their decrease contributes to failed anti-tumor immunity.
在肿瘤中，表达转录因子 TCF-1 的 CD8 T 细胞亚群驱动对免疫检查点阻断的反应。我们研究了在肺腺癌的同源模型中维持这些细胞的机制。对肿瘤抗原特异性 TCF-1 CD8 T 细胞进行纵向采样和单细胞测序表明，虽然肿瘤内 TCF-1 CD8 T 细胞随着肿瘤的进展获得功能失调的特征并减少，但肿瘤引流淋巴结 (dLN) 中的 TCF-1 CD8 T 细胞频率保持稳定。随着时间的推移，两个离散的肿瘤内 TCF-1 CD8 T 细胞亚群发展起来——增殖的 SlamF6 亚群和非循环的 SlamF6 亚群。阻断 dLN 出口会降低肿瘤内 SlamF6 TCF-1 CD8 T 细胞的频率。随着肿瘤的进展，dLN 中的传统 I 型树突状细胞 (cDC1) 的数量减少，而 Flt3L+抗 CD40 治疗恢复了 SlamF6 T 细胞的频率并降低了肿瘤负担。因此，肿瘤 dLN 中的 cDC1 维持了 TCF-1 CD8 T 细胞的储备，其减少导致抗肿瘤免疫失败。
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