肿瘤细胞治疗研究
英文原题：Tertiary lymphoid structures correlate with the therapeutic efficacy and prognosis of resectable esophageal squamous cell carcinoma undergoing neoadjuvant chemoradiotherapy plus immunotherapy.
NRCI治疗相比NCI治疗显著改善了可切除ESCC的预后。TLS的分布和丰度与ESCC的OS明显相关，并在NRCI治疗中作为OS的独立预后指标。NRCI治疗通过促进M-TLS的增殖和活化，延长了OS并增强了抗肿瘤免疫反应。
三级淋巴结构（TLSs）与食管鳞状细胞癌（ESCC）的预后相关，但TLSs的分布、丰度和成熟度是否影响接受新辅助放化疗联合免疫治疗（NRCI）的ESCC患者的疗效和预后仍不清楚。我们探索了TLS特征并将其与患者生存相关联。
2020年9月至2023年5月期间接受新辅助治疗的157例可切除ESCC患者被分为NRCI组（n=49）和新辅助化疗免疫治疗（NCI，n=108）组。采用多重免疫荧光（mIHC）比较NRCI组（n=40）和NCI组（n=40）中TLSs的空间分布和细胞组成。TLSs评分系统评估了肿瘤内区域（T区域）、浸润边缘（IM区域）和瘤周区域（P区域）的TLSs丰度和成熟度。分析了两组间总生存期（OS）和无病生存期（DFS）的差异。此外，对20例未经治疗的ESCC样本进行全外显子测序（WES），以探讨TLS浸润与基因突变之间的关系。
NRCI组的OS和DFS显著优于NCI组，且主要病理缓解（MPR）率更高。MPR患者的OS和DFS显著更长，提示NRCI治疗大幅改善了患者预后（均P <0.05）。TLS丰度在不同组织区域表现出不同的免疫效应：瘤内和浸润边缘的TLS丰度与更长的OS显著相关，而瘤周TLS丰度与更短的OS相关（均P <0.05）。高度成熟的TLS（M-TLS）与更好的OS密切相关（均P <0.05）。在NRCI组中，M-TLS显示出比NCI组更高比例的CD20 + Ki-67 + B细胞、CD21 + 树突状细胞（DCs）、CD4 + Ki-67 + 辅助性T细胞（Th）和CD8 + Ki-67 + 细胞毒性T细胞（均P <0.05），表明NRCI治疗增强了抗肿瘤免疫应答。
BACKGROUND: Tertiary lymphoid structures (TLSs) are linked to prognosis in esophageal squamous cell carcinoma (ESCC), but whether the distribution, abundance, and maturity of TLSs affect therapeutic efficacy and prognosis in ESCC treated with neoadjuvant chemoradiotherapy plus immunotherapy (NRCI) remains unclear. We explored TLS characteristics and correlated them with patient survival. METHODS: A total of 157 resectable ESCC patients treated with neoadjuvant therapy between September 2020 and May 2023 were divided into NRCI (n=49) and neoadjuvant chemoimmunotherapy (NCI, n=108) groups. Multiplex immunofluorescence (mIHC) was employed to compare the spatial distribution and cellular composition of TLSs in the NRCI (n=40) and NCI (n=40) groups. A TLSs scoring system assessed TLSs abundance and maturity across intratumoral regions (T regions), invasive margins (IM regions), and peritumoral regions (P regions). The differences in overall survival (OS) and disease-free survival (DFS) between the two groups were analyzed. Furthermore, whole-exome sequencing (WES) on 20 untreated ESCC samples examined the relationship between TLS infiltration and genetic mutations. RESULTS: The OS and DFS in the NRCI group were significantly superior to the NCI group, with a higher rate of major pathological response (MPR). MPR patients exhibited significantly longer OS and DFS, suggesting that NRCI therapy substantially enhanced patient outcomes (all P <0.05). TLSs abundance exhibited varying immune effects in different tissue regions: intratumoral and invasive margin TLSs abundance was significantly associated with longer OS, while peritumoral TLSs abundance was linked to a shorter OS (all P <0.05). Highly mature TLSs (M-TLSs) were closely associated with a better OS (all P <0.05). In the NRCI group, M-TLSs showed higher proportions of CD20 + Ki-67 + B cells, CD21 + dendritic cells (DCs), CD4 + Ki-67 + helper T cells (Th), and CD8 + Ki-67 + cytotoxic T cells compared to the NCI group (all P <0.05), indicating that NRCI therapy enhanced antitumor immune responses. CONCLUSION: NRCI therapy significantly enhanced the prognosis of resectable ESCCs compared to NCI therapy. The distribution and abundance of TLSs were clearly associated with OS in ESCCs and acted as independent prognostic indicators for OS in NRCI therapy. NRCI therapy extended OS and bolstered antitumor immune responses by facilitating the proliferation and activation of M-TLSs.
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