肿瘤细胞治疗研究
英文原题：Mature tertiary lymphoid structures support B cell-mediated antitumour immunity and are disrupted by neoadjuvant therapy in rectal cancer: a multicentre, retrospective study.
mTLS与增强的B细胞介导的免疫特征和良好预后相关。新辅助治疗后的状态与T细胞浸润增加但TLS存在减少相关。在无应答者中观察到的持续性B细胞激活提出了这样一种可能性，即旨在保护或增强体液免疫的治疗策略可能使这一患者亚群获益。
肿瘤免疫微环境（TIME），特别是三级淋巴结构（TLS）的存在和成熟状态，塑造了抗肿瘤免疫和治疗反应。然而，成熟TLS（mTLS）在直肠癌（RC）中的作用及其受新辅助治疗（neoTx）调控的机制仍不清楚。
在这项多中心回顾性研究中，我们分析了来自两个队列的RC患者。对未接受治疗（NT）的局部晚期直肠癌（LARC）患者进行的多组学分析包括bulk RNA-seq（n = 123）、免疫组织化学和多重免疫荧光（n = 161）、scRNA-seq（n = 10）及配对的scBCR-seq（n = 10）。一个独立的neoTx队列用于评估治疗诱导的免疫变化，包括bulk RNA-seq（n = 19）和免疫组织化学（n = 125）。
mTLS肿瘤的特征是浆细胞和CD8+ T细胞在空间上彼此紧邻。B细胞相关特征——包括浆细胞、生发中心B细胞和滤泡B细胞——以及CD138、IgG和IgA表达在mTLS肿瘤中升高。scRNA-seq和scBCR-seq分析进一步揭示，mTLS肿瘤含有更丰富的浆细胞、更广泛的克隆多样性以及更高比例的IgG+和IgA+浆细胞。CD138高表达与有利生存相关。新辅助治疗后肿瘤显示更高的CD4+、CD8+和CD45RO+ T细胞密度以及更低的mTLS存在。值得注意的是，B细胞基因特征和CD20+细胞密度在新辅助治疗应答者中富集，尽管TLS成熟度无差异。
BACKGROUND: The tumour immune microenvironment (TIME), particularly the presence and maturation of tertiary lymphoid structures (TLS), shapes antitumour immunity and therapy response. However, the role of mature TLS (mTLS) in rectal cancer (RC) and their modulation by neoadjuvant therapy (neoTx) remain unclear. METHODS: In this multicentre, retrospective study, we analysed patients with RC from two cohorts. Multi-omics profiling in patients with locally advanced rectal cancer (LARC) receiving no treatment (NT) included bulk RNA-seq (n = 123), immunohistochemistry and multiplex immunofluorescence (n = 161), scRNA-seq (n = 10) with paired scBCR-seq (n = 10). An independent neoTx cohort was used to assess treatment-induced immune changes, including bulk RNA-seq (n = 19) and immunohistochemistry (n = 125). FINDINGS: mTLS tumours were characterised by plasma cells and CD8 + T cells being located in close spatial proximity to each other. B cell-related signatures-including plasma cells, germinal centre B cells, and follicular B cells-as well as CD138, IgG, and IgA expression were elevated in mTLS tumours. scRNA-seq and scBCR-seq analyses further revealed that mTLS tumours harboured a greater abundance of plasma cells, broader clonal diversity, and a higher proportion of IgG + and IgA + plasma cells. High CD138 expression correlated with favourable survival. Post-neoTx tumours showed higher CD4 + , CD8 + , and CD45RO + T cell densities and lower mTLS presence. Notably, B cell gene signatures and CD20 + cell density were enriched in responders to neoTx, despite no difference in TLS maturation. INTERPRETATION: mTLS are associated with enhanced B cell-mediated immune features and favourable prognosis. Post-neoTx is correlated with increased T cell infiltration but decreased TLS presence. The sustained B cell activation observed in non-responders raises the possibility that therapeutic strategies aimed at preserving or enhancing humoural immunity may benefit this patient subset. FUNDING: This study was supported by grants from the Natural Science Foundation of Beijing (7242034), New Technologies and Businesses of the PLAGH (5156ZE1X).
MEMBER ACCOUNT
登录成功会直接打开下一页。
