PD-1 blockade therapy promotes infiltration of tumor-attacking exhausted T cell clonotypes
PD-1 blockade therapy promotes infiltration of tumor-attacking exhausted T cell clonotypes
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DOI：
10.1016/j.celrep.2022.110331
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发表时间：
2022-02-01
期刊：
影响因子：
8.8
通讯作者：
Togashi, Yosuke
中科院分区：
文献类型：
--
作者：
Nagasaki, Joji;Inozume, Takashi;Togashi, Yosuke
PD-1阻断通过重新激活直接攻击肿瘤微环境（TME）中肿瘤细胞（肿瘤特异性T细胞）的T细胞，对各种类型的癌症发挥临床疗效，肿瘤浸润淋巴细胞（TIL）也包含非特异性旁观者T细胞。在这里，使用单细胞测序，我们表明，TIL包括倾斜的T细胞克隆型，其特征在于耗尽（T-ex）或非耗尽签名（Tnon-ex）。在偏斜的克隆型中，T-ex中的克隆型而非Tnon-ex中的克隆型对自体肿瘤细胞系有反应。在PD-1阻断后，T-ex簇中非预先存在的肿瘤特异性克隆型出现在TME中。无转移的肿瘤引流淋巴结（TDLN）含有相当数量的此类克隆型，而这些克隆型很少在外周血中检测到。我们提出，具有耗尽表型的肿瘤浸润性偏斜T细胞克隆型直接攻击肿瘤细胞，并且PD-1阻断可以促进这种T-ex克隆型的浸润，主要来自TDLN。
PD-1 blockade exerts clinical efficacy against various types of cancer by reinvigorating T cells that directly attack tumor cells (tumor-specific T cells) in the tumor microenvironment (TME), and tumor-infiltrating lymphocytes (TILs) also comprise nonspecific bystander T cells. Here, using single-cell sequencing, we show that TILs include skewed T cell clonotypes, which are characterized by exhaustion (T-ex) or nonexhaustion signatures (Tnon-ex). Among skewed clonotypes, those in the T-ex, but not those in the Tnon-ex, cluster respond to autologous tumor cell lines. After PD-1 blockade, non-preexisting tumor-specific clonotypes in the T-ex cluster appear in the TME. Tumor-draining lymph nodes (TDLNs) without metastasis harbor a considerable number of such clonotypes, whereas these clonotypes are rarely detected in peripheral blood. We propose that tumor-infiltrating skewed T cell clonotypes with an exhausted phenotype directly attack tumor cells and that PD-1 blockade can promote infiltration of such T-ex clonotypes, mainly from TDLNs.