CD39+ tissue-resident memory CD8+ T cells with a clonal overlap across compartments mediate antitumor immunity in breast cancer
CD39+ tissue-resident memory CD8+ T cells with a clonal overlap across compartments mediate antitumor immunity in breast cancer
复制标题
DOI：
10.1126/sciimmunol.abn8390
复制
发表时间：
2022-08-01
影响因子：
24.8
通讯作者：
Shin, Eui-Cheol
中科院分区：
文献类型：
--
作者：
Lee, Yong Joon;Kim, Jee Ye;Shin, Eui-Cheol
尽管免疫检查点抑制剂（ICI）是乳腺癌的标准治疗选择，但它仅对一部分患者有效。为了更好地了解乳腺癌中的抗肿瘤免疫应答，我们检测了早期乳腺癌患者（n = 131）肿瘤、转移性淋巴结（mLN）和外周血中CD 8（+）T细胞的异质性。在组织驻留记忆CD 8（+）T（T-RM）细胞中，包括病毒和肿瘤特异性CD 8（+）T细胞，在肿瘤和mLN中的肿瘤特异性和耗竭亚群中观察到CD 39表达。来自肿瘤和mLN的CD 39（+）T-RM细胞表现出表型相似性，并且克隆性彼此重叠。此外，肿瘤或mLN CD 39（+）T-RM细胞与CD 39（-）T-RM和非T-R（M）细胞在同一区室中克隆性重叠，这意味着组织特异性分化过程。这些亚群间重叠的CD 39（+）T-RM克隆型在外周血中的效应记忆CD 8（+）T细胞中经常检测到，表明系统性克隆重叠。CD 39（+）T-RM细胞在乳腺癌分子亚型中的富集是异质性的，这与抗肿瘤免疫应答在每个亚型中的不同作用有关。PD-1和/或CTLA-4的体外阻断有效地恢复了CD 39（+）T-RM细胞的增殖，并增强了来自肿瘤或mLN的CD 8（+）T细胞的细胞因子产生，特别是在存在CD 39（+）T-RM富集的情况下。这表明CD 39（+）T-RM细胞在ICI处理后具有功能恢复的能力。因此，我们的研究表明，CD 39（+）T-RM细胞与跨区室的克隆重叠是乳腺癌抗肿瘤免疫的关键球员。
Despite being a standard treatment option in breast cancer, immune checkpoint inhibitors (ICIs) are only efficacious for a subset of patients. To gain a better understanding of the antitumor immune response in breast cancer, we examined the heterogeneity of CD8(+) T cells in tumors, metastatic lymph nodes (mLNs), and peripheral blood from patients with early breast cancer (n = 131). Among tissue-resident memory CD8(+) T (T-RM) cells, including virus- and tumor-specific CD8(+) T cells, CD39 expression was observed in a tumor-specific and exhausted subpopulation in both tumors and mLNs. CD39(+) T-RM cells from tumors and mLNs exhibited a phenotypic similarity and clonally overlapped with each other. Moreover, tumor or mLN CD39(+) T-RM cells clonally overlapped with CD39(-) T-RM and non-T-R(M) cells in the same compartment, implying a tissue-specific differentiation process. These inter-subpopulationally overlapping CD39(+) T-RM clonotypes were frequently detected among effector memory CD8(+) T cells in peripheral blood, suggesting a systemic clonal overlap. CD39(+) T-RM cell enrichment was heterogeneous among molecular subtypes of breast cancer, which is associated with the different role of antitumor immune responses in each subtype. In vitro blockade of PD-1 and/or CTLA-4 effectively restored proliferation of CD39(+) T-RM cells and enhanced cytokine production by CD8(+) T cells from tumors or mLNs, particularly in the presence of CD39(+) T-RM enrichment. This suggests that CD39(+) T-RM cells have a capacity for functional restoration upon ICI treatment. Thus, our study indicates that CD39(+) T-RM cells with a clonal overlap across compartments are key players in antitumor immunity in breast cancer.