PO.CL01.12 · 临床研究
空间解析的肿瘤细胞MHC II类分子塑造三阴性乳腺癌的适应性免疫与治疗应答
Spatially resolved tumor-cell MHC class II shapes adaptive immunity and therapeutic response in triple-negative breast cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：MHC II类分子通常仅限于专职抗原递呈细胞。既往TNBC研究聚焦于免疫区室的MHC-II。近期我们利用空间转录组学，发现了异常的肿瘤细胞MHC-II表达。本研究表征了HLA-DRA表达肿瘤细胞周围的免疫结构。
方法：对初治TNBC（Mayo TMA，n=65）及两个新辅助pembrolizumab队列（Mayo n=8；Emory n=4）进行高通量单细胞空间转录组学分析（CosMx TM SMI）。以HLA-DRA高表达肿瘤细胞为参照绘制空间邻域。评估差异表达及适应性免疫基因集评分。采用FinXX（n=114）、I-SPY2（n=364）和Caris CODEai（n=3,662）评估临床相关性。
结果：HLA-DRA高表达肿瘤区域在≤50 μm范围内显著富集适应性免疫亚群，包括B细胞、CD8+ T细胞、NK细胞、巨噬细胞和浆细胞样树突状细胞。在pembrolizumab治疗队列中，应答者表现出更高比例的HLA-DRA高表达肿瘤细胞，以及肿瘤细胞附近更多的B细胞、浆母细胞、CD4+和CD8+ T细胞及巨噬细胞。应答者的肿瘤显示抗原递呈机制、B细胞/浆细胞程序、CXCL13及NOTCH3/DLL1上调。在I-SPY2和FinXX中，较高的HLA-DRA与病理完全缓解及生存改善相关。在CODEai TNBC中，HLA-DRA高表达与更高的CXCL13（中位TPM 7.5对1.1，q<0.05）及更长的总生存期相关（24.2对18.5个月，HR 0.77，95% CI 0.71-0.83，p<0.0001）。该关联为TNBC特异性。高CXCL13同样预示生存改善（26.6对16.5个月，HR 0.64，95% CI 0.59-0.69，p<0.0001）。
结论：肿瘤细胞HLA-DRA表达界定了一个高度有序的适应性免疫生态位，其中紧邻富集有B细胞和活化的T细胞群。适应性免疫程序——包括增强的抗原递呈和CXCL13介导的B细胞/浆细胞通路——在接受化疗和免疫检查点阻断治疗的TNBC队列中一致地与更好的结局相关。异常的肿瘤细胞MHC-II表达可能有助于抗肿瘤免疫，值得作为潜在治疗靶点进一步研究。
查看英文原文 English abstract
Background: MHC class II molecules are normally restricted to professional antigen-presenting cells. Prior TNBC studies have focused on immune-compartment MHC-II. Using spatial transcriptomics, we recently identified aberrant tumor-cell MHC-II expression. Here, we characterized the immune architecture surrounding HLA-DRA-expressing tumor cells.
Methods: High-plex single-cell spatial transcriptomics (CosMx TM SMI) was performed on treatment-naïve TNBC (Mayo TMA, n=65) and two neoadjuvant pembrolizumab cohorts (Mayo n=8; Emory n=4). Spatial neighborhoods were mapped relative to HLA-DRA-high tumor cells. Differential expression and adaptive immune gene-set scores were evaluated. Clinical relevance was assessed using FinXX (n=114), I-SPY2 (n=364), and Caris CODEai (n=3,662).
Results: HLA-DRA-high tumor regions showed significant enrichment of adaptive immune subsets within ≤50 μm, including B cells, CD8 + T cells, NK cells, macrophages, and plasmacytoid dendritic cells. In pembrolizumab-treated cohorts, responders exhibited higher proportions of HLA-DRA-high tumor cells and greater numbers of B cells, plasmablasts, CD4 + and CD8 + T cells, and macrophages near tumor cells. Responders' tumors showed upregulation of antigen-presentation machinery, B-cell/plasma-cell programs, CXCL13, and NOTCH3/DLL1. Across I-SPY2 and FinXX, higher HLA-DRA correlated with pathologic complete response and improved survival. In CODEai TNBC, high HLA-DRA expression correlated with higher CXCL13 (median TPM 7.5 vs. 1.1, q<0.05) and longer overall survival (24.2 vs. 18.5 months, HR 0.77, 95% CI 0.71-0.83, p<0.0001). This association was TNBC-specific. High CXCL13 also predicted improved survival (26.6 vs. 16.5 months, HR 0.64, 95% CI 0.59-0.69, p<0.0001).
Conclusions: Tumor-cell HLA-DRA expression defines a highly organized adaptive immune niche enriched with B cells and activated T-cell populations in close proximity. Adaptive immune programs-including enhanced antigen presentation and CXCL13-mediated B-cell/plasma-cell pathways-consistently associate with improved outcomes across TNBC cohorts treated with chemotherapy and immune checkpoint blockade. Aberrant tumor-cell MHC-II expression may contribute to antitumor immunity and warrants further investigation as a potential therapeutic target.
利益披露 Disclosure
Y. Liu, None..
S. K. Deshmukh, None..
T. Susiriwatananont, None..
B. Wu, None..
H. Joensuu, None..
S. Wu, None..
S. Gandhi, None..
M. Lustberg, None..
G. W. Sledge, None..
E. Thompson, None..
J. Carter, None.
S. Chumsri,
Merck ).
Pfizer ), Other, Consulting fee.
Genentech ), Other, Consulting fee.
Menarini Stemline Other, Consulting fee.
Seagen Other, Consulting fee.
Eisai Other, Consulting fee.
Puma Other.
AstraZeneca/Daiichi Other, Consulting fee.