PO.CL02.01 · 临床研究
腺苷阻断联合FOLFIRINOX化疗可增强小鼠和人胰腺腺癌引流淋巴结中滤泡辅助性T细胞的功能
Adenosine blockade combined with FOLFIRINOX chemotherapy enhances T follicular helper cell function in pancreatic adenocarcinoma draining lymph nodes from mice and humans
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摘要 Abstract
中文摘要
超过90%的胰腺癌为胰腺导管腺癌(PDAC)，这是一种预后差、治疗选择有限的侵袭性疾病。化疗和免疫治疗的疗效均受限于PDAC免疫抑制性肿瘤微环境(TME)。治疗相关的肿瘤细胞死亡导致细胞外腺苷的蓄积，腺苷是PDAC TME中一种强效的免疫抑制性代谢产物；据此，我们研究了在化疗期间阻断腺苷的效果。在PDAC原位小鼠模型中，抑制CD73（负责生成细胞外腺苷的主要酶）联合FOLFIRINOX使肿瘤体积缩小57%(P=0.04)，并与单用FOLFIRINOX治疗相比显著延长生存期。FOLFIRINOX+CD73i显著减少了抑制性SPP1+肿瘤相关巨噬细胞，增强了TME中多种细胞类型的I型和II型干扰素信号，且其作用依赖于CD4+和CD8+ T细胞。为追踪抗原特异性CD4+ T细胞，我们对原位植入的肿瘤细胞进行改造，使其表达一个MHC-II限制性表位，发现FOLFIRINOX+CD73i治疗增加了肿瘤引流淋巴结中的滤泡辅助性T(Tfh)细胞，但这些细胞并未富集四聚体阳性、肿瘤抗原特异性细胞。相反，TME中的Treg细胞富集了四聚体阳性细胞，提示CD73i可能驱动抗原反应性T细胞向抑制性表型发展。在FOLFIRINOX+CD73i基础上加入anti-CCR8以靶向活化T细胞，与单用FOLFIRINOX+CD73i相比显著减小了肿瘤质量(P=0.02)。
为研究CD73i对PDAC患者适应性免疫应答的影响，我们对来自接受新辅助FOLFIRINOX+anti-PD-1+CD73i、FOLFIRINOX+anti-PD-1、单用FOLFIRINOX或未治疗患者的53个肿瘤引流淋巴结进行了基于Xenium影像的空间转录组学分析。与我们的小鼠模型一致，我们发现滤泡内抗原经历性B细胞密度呈显著的CD73i依赖性增加(P=0.037)，同时伴随滤泡内CD8+ T细胞密度的增加(P<0.001)，这可由Tfh细胞功能增强来解释。据此，与FOLFIRINOX+anti-PD-1相比，我们在接受FOLFIRINOX+anti-PD-1+CD73i治疗的肿瘤中发现表达IL-21的Tfh细胞富集。这些结果表明，CD73i可能在PDAC中驱动独特的免疫重塑，增强引流淋巴结中Tfh细胞的功能，但在肿瘤微环境中倾向于抗原特异性Treg的富集。
查看英文原文 English abstract
Over 90% of all pancreatic cancer cases are pancreatic ductal adenocarcinoma (PDAC), an aggressive disease with poor prognosis and limited treatment options. Chemotherapy and immunotherapy efficacy are both limited by the immunosuppressive PDAC tumor microenvironment (TME). Treatment-related tumor cell death leads to accumulation of extracellular adenosine, a potent immunosuppressive metabolite in the PDAC TME; accordingly, we investigated the effects of blocking adenosine during chemotherapy treatment. In an orthotopic murine model of PDAC, CD73 - the primary enzyme responsible for extracellular adenosine - inhibition in combination with FOLFIRINOX reduced tumor size by 57% (P=0.04) and significantly increased survival compared to treatment with FOLFIRINOX alone. FOLFIRINOX+CD73i significantly decreased suppressive SPP1+ tumor-associated macrophages, increased Type I and Type II interferon signaling of multiple cell types in the TME, and was CD4+ and CD8+ T cell dependent. To track antigen-specific CD4+ T cells, we engineered expression of an MHC-II restricted epitope in orthotopically implanted tumor cells and found that FOLFIRINOX+CD73i treatment increased follicular helper T (Tfh) cells in tumor-draining lymph nodes but that these cells were not enriched for tetramer-positive, tumor antigen-specific cells. In contrast, Treg cells in the TME were enriched for tetramer-positive cells suggesting that CD73i may drive antigen-reactive T cells toward a suppressor phenotype. Targeting activated T cells by adding anti-CCR8 to FOLFIRINOX+CD73i significantly decreased tumor masses compared to FOLFIRINOX+CD73i alone (P=0.02).
To investigate the effect of CD73i on adaptive immune responses in PDAC patients, we performed Xenium image-based spatial transcriptomics on 53 tumor-draining lymph nodes from patients treated with neoadjuvant FOLFIRINOX+anti-PD-1+CD73i, FOLFIRINOX+anti-PD-1, FOLFIRINOX alone, or untreated. In line with our mouse model, we found a significant CD73i-dependent increase in intra-follicular antigen-experienced B cell density (P=0.037) with a concomitant increase in intra-follicular CD8+ T cell density (P<0.001), which could be explained by enhanced function of Tfh cells. Accordingly, we found enrichment in IL-21 expressing Tfh cells in tumors treated with FOLFIRINOX+anti-PD-1+CD73i compared to FOLFIRINOX+anti-PD-1. These results indicate that CD73i may drive distinct immune remodeling in PDAC, boosting Tfh cell function in draining lymph nodes but favoring antigen-specific Treg enrichment in the tumor microenvironment.
利益披露 Disclosure
M. K. Srienc, None..
E. Abt, None.