PDF(Pubmed)
Abstract：
BACKGROUND: Tertiary lymphoid structures (TLSs) are thought to stimulate antitumor immunity and positively impact prognosis and response to immune checkpoint blockade. In gastric cancers (GCs), however, TLSs are predominantly found in GC with poor prognosis and limited treatment response. We, therefore, hypothesize that immune cell composition and function of TLS depends on tumor location and the tumor immune environment.
METHODS: Spatial transcriptomics and immunohistochemistry were used to characterize the phenotype of CD45+ immune cells inside and outside of TLS using archival resection specimens from GC primary tumors and peritoneal metastases.
RESULTS: We identified significant intrapatient and interpatient diversity of the cellular composition and maturation status of TLS in GC. Tumor location (primary vs metastatic site) accounted for the majority of differences in TLS maturity, as TLS in peritoneal metastases were predominantly immature. This was associated with higher levels of tumor-infiltrating macrophages and Tregs and less plasma cells compared with tumors with mature TLS. Furthermore, mature TLSs were characterized by overexpression of antitumor immune pathways such as B cell-related pathways, MHC class II antigen presentation while immature TLS were associated with protumor pathways, including T cell exhaustion and enhancement of DNA repair pathways in the corresponding cancer.
CONCLUSIONS: The observation that GC-derived peritoneal metastases often contain immature TLS which are associated with immune suppressive regulatory tumor-infiltrating leucocytes, is in keeping with the lack of response to immune checkpoint blockade and the poor prognostic features of peritoneal metastatic GC, which needs to be taken into account when optimizing immunomodulatory strategies for metastatic GC.
METHODS: Spatial transcriptomics and immunohistochemistry were used to characterize the phenotype of CD45+ immune cells inside and outside of TLS using archival resection specimens from GC primary tumors and peritoneal metastases.
RESULTS: We identified significant intrapatient and interpatient diversity of the cellular composition and maturation status of TLS in GC. Tumor location (primary vs metastatic site) accounted for the majority of differences in TLS maturity, as TLS in peritoneal metastases were predominantly immature. This was associated with higher levels of tumor-infiltrating macrophages and Tregs and less plasma cells compared with tumors with mature TLS. Furthermore, mature TLSs were characterized by overexpression of antitumor immune pathways such as B cell-related pathways, MHC class II antigen presentation while immature TLS were associated with protumor pathways, including T cell exhaustion and enhancement of DNA repair pathways in the corresponding cancer.
CONCLUSIONS: The observation that GC-derived peritoneal metastases often contain immature TLS which are associated with immune suppressive regulatory tumor-infiltrating leucocytes, is in keeping with the lack of response to immune checkpoint blockade and the poor prognostic features of peritoneal metastatic GC, which needs to be taken into account when optimizing immunomodulatory strategies for metastatic GC.
摘要：
背景：三级淋巴结构（TLSs）被认为可以刺激抗肿瘤免疫，并对预后和对免疫检查点阻断的反应产生积极影响。在胃癌（GC）中，然而,TLS主要在GC中发现，预后差，治疗反应有限。我们,因此,假设TLS的免疫细胞组成和功能取决于肿瘤位置和肿瘤免疫环境。
方法：使用来自GC原发肿瘤和腹膜转移的档案切除标本，使用空间转录组学和免疫组织化学来表征TLS内外CD45免疫细胞的表型。
结果：我们确定了GC中TLS的细胞组成和成熟状态的显着患者内部和患者间多样性。肿瘤位置（原发与转移部位）占TLS成熟度的大多数差异，因为腹膜转移瘤中的TLS主要是未成熟的。与具有成熟TLS的肿瘤相比，这与更高水平的肿瘤浸润巨噬细胞和Treg以及更少的浆细胞有关。此外，成熟的TLS的特征是抗肿瘤免疫途径如B细胞相关途径的过度表达，MHCII类抗原呈递，而未成熟的TLS与蛋白途径相关，包括T细胞耗尽和相应癌症中DNA修复途径的增强。
结论：观察到GC来源的腹膜转移通常含有未成熟的TLS，这些TLS与免疫抑制性调节性肿瘤浸润的白细胞有关，与缺乏对免疫检查点阻断的反应和腹膜转移性GC的不良预后特征保持一致，在优化转移性GC的免疫调节策略时需要考虑这一点。
方法：使用来自GC原发肿瘤和腹膜转移的档案切除标本，使用空间转录组学和免疫组织化学来表征TLS内外CD45免疫细胞的表型。
结果：我们确定了GC中TLS的细胞组成和成熟状态的显着患者内部和患者间多样性。肿瘤位置（原发与转移部位）占TLS成熟度的大多数差异，因为腹膜转移瘤中的TLS主要是未成熟的。与具有成熟TLS的肿瘤相比，这与更高水平的肿瘤浸润巨噬细胞和Treg以及更少的浆细胞有关。此外，成熟的TLS的特征是抗肿瘤免疫途径如B细胞相关途径的过度表达，MHCII类抗原呈递，而未成熟的TLS与蛋白途径相关，包括T细胞耗尽和相应癌症中DNA修复途径的增强。
结论：观察到GC来源的腹膜转移通常含有未成熟的TLS，这些TLS与免疫抑制性调节性肿瘤浸润的白细胞有关，与缺乏对免疫检查点阻断的反应和腹膜转移性GC的不良预后特征保持一致，在优化转移性GC的免疫调节策略时需要考虑这一点。
