LBPO.CL04 · 临床研究 · Late-Breaking

靶向XPO1重编程免疫微环境并使胰腺导管腺癌对免疫检查点阻断敏感

Targeting XPO1 reprograms immune microenvironment and confers sensitivity to immune checkpoint blockade in pancreatic ductal adenocarcinoma

编号 LB416 展板 6 时间 4/22 09:00–12:00 区域 Section 51 主讲 Md Hafiz Uddin, PhD

分会场 Late-Breaking Research: Clinical Research 4

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作者与单位 Authors & Affiliations

Md Hafiz Uddin¹, Mohammed Najeeb Al Hallack¹, Misako Nagasaka², Sahar F. Bannoura¹, Husain Y. Khan¹, Amro Aboukameel¹, Fulya K. Alkan¹, Hilmi K. Alkan¹, Khalil Choucair¹, M Wasif Saif¹, Bin Bao¹, Ibrahim Azar¹, Eliza W. Beal¹, Miguel Tobon¹, Steve Kim¹, Amr Mohamed³, Gregory Dyson¹, Rafic Beydoun¹, Ramzi M. Mohammad¹, Herbert Chen⁴, Bassel El-Rayes F. El-Rayes⁴, Philip A. Philip⁵, Boris C. Pasche¹, Hasan Korkaya¹, Asfar S. Azmi¹

¹Barbara Ann Karmanos Cancer Institute, Detroit, MI,²Detroit Medical Center, Detroit, MI,³UH Seidman Cancer Center, University Hospitals, Case Western Reserve University, Cleveland, OH,⁴O’Neill Comprehensive Cancer Center, University of Alabama, Birmingham, AL,⁵Henry Ford Cancer Institute, Henry Ford Health, Detroit, MI

摘要 Abstract

中文摘要

背景：胰腺导管腺癌（PDAC）是一种高度致死的恶性肿瘤，由于其深度免疫抑制和免疫排斥的肿瘤微环境（TME），在很大程度上对免疫检查点阻断仍然难治。核质转运对于肿瘤和基质中的免疫信号传导至关重要。输出蛋白1（XPO1）是主要的核输出受体，在PDAC中过表达，并与治疗耐药相关，但其在PDAC免疫发病机制中的作用尚未明确。方法：在本研究中，我们利用了同基因型和基因工程小鼠模型（GEMMs；KPC（Kras/p53/Cre））、数字空间图谱（DSP；转录组学/蛋白质组学）和单核RNA测序（snRNAseq）。用选择性XPO1抑制剂Selinexor以及吉西他滨-白蛋白结合型紫杉醇处理PDAC细胞，并通过bulk RNA测序进行分析。接受Selinexor和吉西他滨-白蛋白结合型紫杉醇的KPC肿瘤进行了snRNAseq、DSP、免疫组织化学（IHC）和免疫表型分析。在Pan02同基因型模型中，将Selinexor与抗PD-1抗体联合，通过流式细胞术定量肿瘤生长以及肿瘤和脾脏免疫亚群。结果：用Selinexor和吉西他滨-白蛋白结合型紫杉醇处理PDAC诱导了深度免疫重编程，其特征为固有免疫和适应性免疫应答的广泛重塑。我们的转录组学和流式细胞术分析显示具有抗肿瘤免疫功能、抗原呈递和细胞毒性T细胞激活的免疫细胞富集。与这些数据一致，对KPC肿瘤的snRNAseq和IHC分析显示瘤内CD4+和CD8+ T细胞浸润增加，T细胞和B细胞相关转录本（CD3d、CD3e、CD4、CD8a、CD8b1、CD19）表达升高，同时炎性单核细胞标志物Ly6C1上调，表明在致密的促纤维增生性基质内效应淋巴细胞群和抗肿瘤单核细胞发生协调扩增。此外，DSP显示Selinexor和吉西他滨-白蛋白结合型紫杉醇增强了肿瘤和基质区室中与MHC II类介导的抗原加工和白细胞激活相关的通路。Selinexor和吉西他滨-白蛋白结合型紫杉醇处理抑制了免疫抑制性几丁质酶样蛋白Chil3的表达，这已通过IHC、蛋白质印迹和qPCR验证，提示PDAC TME中促肿瘤髓系信号传导的减弱。一致地，在Pan02模型中，Selinexor与抗PD-1治疗联合显著减少了肿瘤生长而无明显毒性，并将髓系细胞群重编程为Ly6ChiCd11b+表型。结论：总之，这些数据将XPO1驱动的核输出确定为PDAC免疫逃逸的核心上游调控因子，并支持在胰腺癌中对XPO1抑制剂与免疫检查点阻断联合方案进行临床检验。正在多种临床前模型中进行的验证正为计划中的临床试验提供依据。

查看英文原文 English abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy that remains largely refractory to immune checkpoint blockade, owing to a profoundly immunosuppressive and immune excluded tumor microenvironment (TME). Nuclear cytoplasmic transport is essential for immune signaling in tumor and stroma. Exportin 1 (XPO1), the dominant nuclear export receptor, is overexpressed in PDAC and has been linked to therapeutic resistance, yet its role in PDAC immunopathogenesis has not been defined. Methods: In this study, we have utilized syngeneic and genetically engineered mouse models (GEMMs; KPC (Kras/p53/Cre)), digital spatial profiling (DSP; transcriptomics/proteomics), and single-nucleus RNA sequencing (snRNAseq). PDAC cells were treated with the selective XPO1 inhibitor Selinexor and Gemcitabine-nab-paclitaxel and profiled by bulk RNA sequencing. KPC tumors receiving Selinexor and Gemcitabine-nab-paclitaxel underwent snRNAseq, DSP, immunohistochemistry (IHC), and immune phenotyping. In Pan02 syngeneic model, Selinexor was combined with anti PD-1 antibody and tumor growth, and tumor and splenic immune subsets were quantified by flow cytometry. Results: Treatment of PDAC with Selinexor and Gemcitabine-nab-paclitaxel induced profound immune reprogramming characterized by broad remodeling of innate and adaptive immune responses. Our transcriptomics and flow cytometry analyses revealed enrichment of immune cells with anti-tumor immune function, antigen presentation and cytotoxic T cell activation. In line with these data, snRNAseq and IHC analysis of KPC tumors demonstrated increased intratumoral CD4+ and CD8+ T cell infiltration and elevated expression of T and B cell-associated transcripts (CD3d, CD3e, CD4, CD8a, CD8b1, CD19) together with upregulation of inflammatory monocyte marker Ly6C1, indicating coordinated expansion of effector lymphoid populations and anti-tumorigenic monocytes within a dense desmoplastic stroma. Furthermore, DSP showed that Selinexor and Gemcitabine-nab-paclitaxel enhanced pathways related to MHC class II-mediated antigen processing and leukocyte activation across both tumor and stromal compartments. Selinexor and Gemcitabine-nab-paclitaxel treatment suppressed the expression of the immunosuppressive chitinase-like protein Chil3, as this was validated by IHC, western blot and qPCR suggesting attenuation of pro-tumor myeloid signaling in PDAC TME. Consistently, Selinexor combined with anti-PD-1 therapy in Pan02 models significantly reduced tumor growth without much toxicity and reprogrammed myeloid cell populations toward Ly6ChiCd11b+ phenotype. Conclusions: Together, these data identify XPO1 driven nuclear export as a central upstream regulator of PDAC immune evasion and support clinical testing of XPO1 inhibitor immune checkpoint blockade combinations in pancreatic cancer. Ongoing validation in diverse preclinical models is informing planned clinical trials.

利益披露 Disclosure

M. Uddin, None. M. N. Al Hallack, Ipsen Other, Speaker. AstraZeneca Other, Speaker. Guardant Health Other, Speaker. Pfizer Other, Speaker. Takeda Other, Speaker. M. Nagasaka, AstraZeneca Other, Consulting or Advisory Role. Caris Life Sciences Other, Consulting or Advisory Role. Daiichi Sankyo Other, Consulting or Advisory Role. Takeda Other, Consulting or Advisory Role. Novartis Other, Consulting or Advisory Role. EMD Serono Other, Consulting or Advisory Role. Janssen Other, Consulting or Advisory Role. Pfizer Other, Consulting or Advisory Role. Lilly Other, Consulting or Advisory Role. Genentech Other, Consulting or Advisory Role. Mirati Therapeutics Other, Consulting or Advisory Role. Bristol Myers Squibb USA Other, Consulting or Advisory Role. Regeneron Other, Consulting or Advisory Role. Blueprint Medicines Other, Speaker. Takeda Other, Speaker. Janssen Other, Speaker. Mirati Therapeutics Other, Speaker. Tempus ). Anheart Therapeutics Jun Gong Travel. Astellas Pharma Other, Honoraria. S. F. Bannoura, None.. H. Y. Khan, None.. A. Aboukameel, None.. F. K. Alkan, None.. H. K. Alkan, None.. K. Choucair, None. M. Saif, US World Meds Other, Advisory Board. Amal Therapeutics ). Genentech Inc. ). IDEAYA ). SpringWorks Therapeutics ). Yivia ). HCW Biologics ). FLASCO Other, Speaker. Uptodate Other, Honorarium. B. Bao, None. I. Azar, MJH Life Sciences Other, Honoraria. AstraZeneca Other, Consulting or Advisory Role. Genmab Nishant Gandhi Other, Consulting or Advisory Role. Caris Life Sciences Employment. E. W. Beal, None.. M. Tobon, None.. S. Kim, None.. A. Mohamed, None.. G. Dyson, None.. R. Beydoun, None.. R. M. Mohammad, None.. H. Chen, None. B. F. El-Rayes, Seattle Genetics ), Other, Speaker. Exelixis Other, Advisory Board. Beigene Other, Advisory Board. AstraZeneca Other, Advisory Board. Bristol-Myers Squibb ). Merck ). AstraZeneca ). Boehringer Ingelheim ). P. A. Philip, Bayer Other, Honoraria. Ipsen Other, Honoraria. Incyte Other, Honoraria. Taiho Pharmaceutical Other, Honoraria. Astellas Pharma Other, Honoraria. BioNTech SE Other, Honoraria. Novocure Other, Honoraria. TriSalus Life Sciences Other, Honoraria. SERVIER Other, Honoraria. Seagen Other, Honoraria. Celgene Other, Consulting or Advisory Role. Ipsen Other, Consulting or Advisory Role. Merck Other, Consulting or Advisory Role. Daiichi Sankyo Other, Consulting or Advisory Role. SynCoreBio Other, Consulting or Advisory Role. Novartis (Inst) ). Regeneron (Inst) ). Genentech (Inst) ). Halozyme (Inst) ). Lilly (Inst) ). B. C. Pasche, TheraBionic Employment, Stock, Other Business Ownership, Other, Leadership. Merck & Co Inc ). Roche ). Novartis ). AstraZeneca ). Bristol Myers Squibb Co ). H. Korkaya, None. A. S. Azmi, Gerson Lehrman Group Other, Consulting or Advisory Role. Guidepoint Inc Other, Consulting or Advisory Role. Purple Biotech ). FanWave ). Colorado chromatography ). Blackstone Therapeutics ).

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