PO.CL02.01 · 临床研究
FOLFIRINOX加nivolumab促进交界可切除胰腺腺癌瘤内淋巴样聚集体产生浆细胞
FOLFIRINOX plus nivolumab promotes plasma cell production from intra-tumoral lymphoid aggregates in borderline resectable pancreatic adenocarcinoma
该海报暂无可下载的资料
AACR 官方页面
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：尽管联合化疗和免疫检查点抑制剂在其他实体瘤中取得成功，但在胰腺导管腺癌（PDAC）中显示出的获益有限。然而，大多数研究是在晚期疾病中进行的。在一项1b/2期研究者发起的临床试验中，我们评估了新辅助FOLFIRINOX（FFX）加nivolumab（nivo）在交界可切除（BR）PDAC患者中的免疫学效应。
方法：通过采用CIBERSORT白细胞去卷积的批量RNA测序、浆细胞的免疫组化（IHC）定量和淋巴样聚集体（LAs）表征，以及10x Xenium空间转录组学（ST）分析LA组织结构，对切除的肿瘤组织进行分析。同时，使用Xenium ST对来自未治疗、仅FFX和FFX+nivo队列的肿瘤引流淋巴结（TDLN）核心进行分析。
结果：在配对的治疗前和治疗后样本中，瘤内CD8 T细胞和浆细胞同时增加。与历史FFX对照相比，nivo治疗的肿瘤具有显著更高的浆细胞丰度（p=0.002）和适度的CD8 T细胞增加（p=0.037）。IHC显示浆细胞丰度与缺乏生发中心样结构的致密瘤内LAs相关（p<0.001），与滤泡外B细胞分化一致。ST在肿瘤床内识别出具有高浆细胞与B细胞比率（PBRs）的不规则LAs，富含终末耗竭的CD8 T细胞，而祖细胞耗竭的CD8 T细胞和中央记忆CD4 T细胞减少。与历史FFX对照相比，nivo治疗患者的TDLN滤泡中浆细胞再次富集（p=0.049），且PBR显著更高（p=0.035）。然而，淋巴结滤泡内的CD8 T细胞和记忆B细胞密度降低（分别为p<0.001和p=0.005）。滤泡辅助性T（Tfh）细胞在抗原特异性B细胞和CD8 T细胞之间提供关键联系；因此，与单用FFX相比，接受FFX+nivo治疗患者的TDLN Tfh细胞中IL-21表达减少（p<0.0001）。
结论：BR PDAC中新辅助FFX加nivo与无序的瘤内LAs、滤泡外样浆细胞分化以及肿瘤床内终末耗竭CD8 T细胞的积累相关。nivo治疗患者的TDLN滤泡也显示出浆细胞偏向、高PBR的结构，但CD8 T细胞和记忆B细胞密度降低，以及Tfh细胞中IL-21表达的选择性丧失。这些特征可能代表了PDAC中有效的基于抗PD-1的化学免疫治疗的障碍。
查看英文原文 English abstract
Background: Combination chemotherapy and immune checkpoint inhibitors have shown limited benefit in pancreatic ductal adenocarcinoma (PDAC) despite their success in other solid tumors. However, most studies were conducted in advanced disease. In a phase 1b/2 investigator-initiated clinical trial, we evaluated immunologic effects of neoadjuvant FOLFIRINOX (FFX) plus nivolumab (nivo) in patients with borderline-resectable (BR) PDAC.
Methods: Resected tumor tissue was analyzed by bulk RNA sequencing with CIBERSORT leukocyte deconvolution, immunohistochemical (IHC) quantification of plasma cells and characterization of lymphoid aggregates (LAs), and 10x Xenium spatial transcriptomics (ST) to investigate LA organization. In parallel, tumor draining lymph node (TDLN) cores from untreated, FFX-only, and FFX+nivo cohorts were profiled with Xenium ST.
Results: Across paired pre- and post-treatment samples, intra-tumoral CD8 T cells and plasma cells increased concurrently. Compared with historical FFX controls, nivo-treated tumors had significantly higher plasma cell abundance (p=0.002) and a modest CD8 T cell increase (p=0.037). IHC revealed that plasma cell abundance correlated with dense intra-tumoral LAs lacking germinal center-like structures (p<0.001), consistent with extrafollicular B cell differentiation. ST identified irregular LAs within the tumor bed with high plasma cell to B cell ratios (PBRs) enriched for terminally exhausted CD8 T cells and de-enriched for progenitor exhausted CD8 T cells and central memory CD4 T cells. In TDLN follicles from nivo-treated patients compared to historical FFX controls, plasma cells were again enriched (p=0.049), and PBR was significantly higher (p=0.035). However, CD8 T cell and memory B cell density decreased within the lymph node follicles (p<0.001 and p=0.005, respectively). T follicular helper (Tfh) cells provide a critical link between antigen-specific B cells and CD8 T cells; accordingly, IL-21 expression was de-enriched in TDLN Tfh cells from patients treated FFX+nivo compare to FFX alone (p<0.0001).
Conclusion: Neoadjuvant FFX plus nivo in BR PDAC is associated with disorganized intra-tumoral LAs, extrafollicular-like plasma cell differentiation, and accumulation of terminally exhausted CD8 T cells within the tumor bed. TDLN follicles in nivo-treated patients also showed plasma cell-skewed, high-PBR architecture, but with reduced CD8 T cell and memory B cell density and selective loss of IL-21 expression in Tfh cells. These features may represent barriers to effective anti-PD-1-based chemoimmunotherapy in PDAC.
利益披露 Disclosure
S. Zheng, None..
J. Link, None..
A. Premji, None..
M. Srienc, None..
M. Hammons, None..
S. Kim, None..
D. Dawson, None..
Z. Wainberg, None..
T. Donahue, None.