PO.IM01.04 · 免疫学

反复RFA重塑PDAC微环境并与CSF1R阻断和检查点抑制协同增强抗肿瘤免疫

Repeated RFA remodels the PDAC microenvironment and synergizes with CSF1R blockade and checkpoint inhibition to enhance anti-tumor immunity

编号 2857 展板 30 时间 4/20 02:00–05:00 区域 Section 8 主讲 Lincoln Strickland, BS

分会场 Immune Mechanisms Invoked by Other Therapies and Exposures

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作者与单位 Authors & Affiliations

Lincoln Strickland¹, Wendao Liu², Casey Van Kirk¹, Shwetapadma Dash¹, MacKenzie Demmel¹, Alyssa Waller¹, Nicolette R. Mardik³, Jesse Cox¹, Curtis J. Wray⁴, Zhongming Zhao⁵, Nirav Thosani⁶, Jennifer Bailey-Lundberg¹

¹University of Nebraska Medical Center, Omaha, NE,²The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX,³The University of Texas Health Science Center, Houston, TX,⁴Assistant Professor, Dept. of Surgery, UT Health Science Ctr. at Houston, Houston, TX,⁵Assoc. Professor, Biomedical Informatics and Cancer Bio., University of Texas Health Science Center at Houston, Houston, TX,⁶University of Texas Health Science Center at Houston, Houston, TX

摘要 Abstract

中文摘要

背景：胰腺导管腺癌（PDAC）以极度免疫抑制的肿瘤微环境（TME）为特征。在大多数病例中，治疗是姑息性的，因为很少有被证明能改善临床结局的有效治疗选择。我们此前证明，单次射频消融（RFA）疗程是安全的，可诱导肿瘤坏死、增强免疫细胞浸润（包括远隔效应），并与免疫检查点阻断（ICB）协同进一步抑制肿瘤生长。假设：我们提出，反复RFA疗程将更有效地抑制肿瘤进展、放大免疫细胞募集并增强对免疫治疗的反应性。方法：使用双侧荷瘤Kras G12D；Trp53 R172H/+；Pdx1:Cre同基因PDAC模型，我们比较了单次与3次反复RFA疗程后的肿瘤反应。使用单细胞RNA测序和细胞因子谱分析表征TME重塑。鉴于我们此前关于单次RFA疗程+ICB的发现，我们评估了反复RFA联合ICB，并测试了添加CSF1R阻断（PLX3397）是否能抵消RFA诱导的髓系免疫抑制。结果：与单次RFA疗程相比，反复RFA显著降低了肿瘤生长速率，并增加了治疗侧和对侧病灶的肿瘤坏死。scRNA-seq和细胞因子分析显示，反复RFA升高了Csf1水平，通过Csf1/Csf1r轴促进免疫抑制性Csf1r+ M2样巨噬细胞的分化。虽然反复RFA联合ICB相比任一单独治疗改善了肿瘤控制，但添加CSF1R抑制进一步增强了疗效。三联组合（反复RFA + ICB + 抗CSF1R）产生了最大的肿瘤体积和重量减少，并带来了最显著的TME重塑。结论：反复RFA加剧肿瘤坏死、抑制肿瘤进展并重塑PDAC TME，但同时诱导了代偿性的Csf1/Csf1r驱动的M2样巨噬细胞反应。通过CSF1R阻断进行巨噬细胞重编程增强了RFA和ICB介导的抗肿瘤免疫。这些发现支持将反复局部消融治疗与髓系靶向药物和检查点阻断相结合，以改善对胰腺癌的免疫控制。

查看英文原文 English abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is defined by a profoundly immunosuppressive tumor microenvironment (TME). In the majority of cases, treatment is palliative as there are few effective therapeutic options shown to improve clinical outcomes. We previously demonstrated that a single radiofrequency ablation (RFA) session is safe, induces tumor necrosis, enhances immune cell infiltration, including an abscopal effect, and synergizes with immune checkpoint blockade (ICB) to further suppress tumor growth. Hypothesis: We proposed that repeated RFA sessions would more effectively restrain tumor progression, amplify immune cell recruitment, and enhance responsiveness to immunotherapy. Methods: Using a bilateral tumor-bearing Kras G12D ; Trp53 R172H/+; Pdx1 :Cre syngeneic PDAC model, we compared tumor responses following single versus 3 repeated RFA sessions. Single-cell RNA sequencing and cytokine profiling were used to characterize TME remodeling. Given our prior findings with a single RFA session + ICB, we evaluated repeated RFA in combination with ICB and tested whether adding CSF1R blockade (PLX3397) could counteract RFA-induced myeloid immune suppression. Results: Repeated RFA significantly reduced tumor growth rates and increased tumor necrosis in both treated and contralateral lesions compared to a single RFA session. scRNA-seq and cytokine analysis revealed that repeated RFA elevated Csf1 levels, promoting differentiation of immune suppressive Csf1r+ M2-like macrophages via the Csf1/Csf1r axis. While repeated RFA combined with ICB improved tumor control compared with either therapy alone, the addition of CSF1R inhibition further enhanced efficacy. The triple combination (repeated RFA + ICB + anti-CSF1R) produced the greatest reduction in tumor volume and weight and yielded the most pronounced remodeling of the TME. Conclusions: Repeated RFA intensifies tumor necrosis, suppresses tumor progression, and remodels the PDAC TME, but concurrently induces a compensatory Csf1/Csf1r-driven M2-like macrophage response. Macrophage reprogramming through CSF1R blockade enhances both RFA- and ICB-mediated anti-tumor immunity. These findings support integrating repeated local ablative therapy with myeloid-targeting agents and checkpoint blockade to improve immunologic control of pancreatic cancer.

利益披露 Disclosure

L. Strickland, None.. W. Liu, None.. C. Van Kirk, None.. S. Dash, None.. N. R. Mardik, None.. J. Cox, None. N. Thosani, ROSEAID Inc Stock Option, Other, Creatorship rights. ALPFA Medical Stock Option. J. Bailey-Lundberg, None.

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