Wakasu Sho, Tagawa Tetsuzo, Haratake Naoki, Kinoshita Fumihiko, Oku Yuka, Ono Yuki, Takenaka Tomoyoshi, Oda Yoshinao, Shimokawa Mototsugu, Mori Masaki
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan.
Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Cancer Immunol Immunother. 2023 Jun;72(6):1823-1834. doi: 10.1007/s00262-022-03353-8. Epub 2023 Jan 23.
Ectopic lymphoid formations are called tertiary lymphoid structures (TLSs). TLSs in cancer have been reported to be associated with good prognosis and immunotherapy response. However, the relationship between TLSs and lymph node (LN) metastasis is unclear.
We analyzed 218 patients with radically resected lung adenocarcinoma. TLSs were defined as the overlap of T cell zone and B cell zone. Granzyme B cells were defined as cytotoxic lymphocytes. We evaluated phenotypes of lymphocytes in TLSs, tumor-infiltrating lymphocytes (TILs) and LNs by immunohistochemistry. We divided the patients into mature TLS (DC-Lamp high) and immature TLS (DC-Lamp low) groups. The relationship between TLS maturation and clinicopathological factors was analyzed.
The mature TLS group was associated with significantly lower frequency of LN metastasis (P < 0.0001) and early cancer stage (P = 0.0049). The mature TLS group had significantly more CD8 (P = 0.0203) and Foxp3 (P = 0.0141) cells in TILs than the immature TLS group had. Mature TLSs were independently associated with a favorable overall survival (hazard ratio [HR] = 0.17, P = 0.0220) and disease-free survival (HR = 0.54, P = 0.0436). Multivariate analysis showed that mature TLS was an independent low-risk factor for LN metastasis (odds ratio = 0.06, P = 0.0003). The number of cytotoxic lymphocytes in LNs was higher in the mature TLS group than in the immature group (20.0 vs. 15.1, P = 0.017).
Mature TLSs were associated with an increased number of cytotoxic lymphocytes in draining LNs, a lower frequency of LN metastasis, and favorable outcomes. Mature TLSs may support antitumor immunity by lymphocyte activation.
异位淋巴组织形成被称为三级淋巴结构（TLSs）。据报道，癌症中的TLSs与良好的预后和免疫治疗反应相关。然而，TLSs与淋巴结（LN）转移之间的关系尚不清楚。
我们分析了218例接受根治性切除的肺腺癌患者。TLSs被定义为T细胞区和B细胞区的重叠区域。颗粒酶B细胞被定义为细胞毒性淋巴细胞。我们通过免疫组织化学评估了TLSs、肿瘤浸润淋巴细胞（TILs）和LN中淋巴细胞的表型。我们将患者分为成熟TLS（DC-Lamp高）组和不成熟TLS（DC-Lamp低）组。分析了TLS成熟与临床病理因素之间的关系。
成熟TLS组的LN转移频率显著较低（P < 0.0001），且癌症分期较早（P = 0.0049）。成熟TLS组的TILs中CD8（P = 0.0203）和Foxp3（P = 0.0141）细胞显著多于不成熟TLS组。成熟TLSs与良好的总生存期（风险比[HR] = 0.17，P = 0.0220）和无病生存期（HR = 0.54，P = 0.0436）独立相关。多变量分析显示，成熟TLS是LN转移的独立低风险因素（比值比 = 0.06，P = 0.0003）。成熟TLS组LN中的细胞毒性淋巴细胞数量高于不成熟组（20.0对15.1，P = 0.017）。
成熟TLSs与引流LN中细胞毒性淋巴细胞数量增加、LN转移频率降低和良好预后相关。成熟TLSs可能通过淋巴细胞激活来支持抗肿瘤免疫。
