奥沙利铂治疗结直肠癌腹膜转移诱导生物标志物预测免疫检查点阻断反应

IF 5 2区医学 Q2 Medicine

Translational Oncology Pub Date : 2025-07-01 DOI:10.1016/j.tranon.2025.102464

Alexander Constantinides , Nico Lansu , Peter Mosen , Paulien Rauwerdink , Esther Strating , Franziska Völlmy , Maaike Nederend , Jeanette H.W. Leusen , Koen Rovers , Emma Wassenaar , Robin Lurvink , Maarten Altelaar , Simon Nienhuijs , Rene Wiezer , Inne H.M. Borel Rinkes , Djamila Boerma , Geert J.P.L. Kops , Ignace de Hingh , Onno Kranenburg

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引用次数: 0

摘要

背景：结直肠癌（CRC）患者伴不可手术腹膜转移（PM）预后不佳，治疗选择有限。通常应用奥沙利铂局部治疗CRC-PM，但缺乏指导患者选择或提示潜在有效联合治疗的生物标志物。一种新的潜在有效的治疗策略是加压腹腔喷雾化疗（PIPAC），其中CRC-PM暴露于高浓度局部应用奥沙利铂的循环治疗中。然而，目前尚不清楚CRC-PM是否以及如何对PIPAC产生反应。在这里，我们从20名接受PIPAC联合奥沙利铂治疗CRC-PM的患者中生成了一个生物库。生物库包含每位患者下午3点的活检，在每个治疗周期之前重复取样，以及腹水。采用浅层单细胞核型测序（sc-karyoSeq）分析抗肿瘤作用。通过rna测序和蛋白质组学来评估基因和蛋白质表达的变化。采用免疫组化方法评估治疗引起的组织组织学变化。用腹水评价免疫球蛋白含量和反应性。结果pipac降低了pipac存活肿瘤细胞的基因组异质性和非整倍体评分。此外，PIPAC降低了免疫抑制信号（缺氧、白细胞介素-10、转化生长因子β），并诱导B和T淋巴细胞的涌入，这些淋巴细胞组织成转移相关的三级淋巴结构（TLS）。TLS是预测免疫检查点抑制剂（ICIs）应答的生物标志物。驻留在pipac诱导的TLS中的T细胞表达高水平的检查点PD-1、TIGIT和EBI3。PIPAC还引起浆细胞产生肿瘤反应性抗体。结论pipac具有一定的抗肿瘤活性，可诱导免疫参数预测免疫应答。因此，不能手术的CRC-PM患者可能受益于PIPAC联合ICIs。

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Treatment of colorectal peritoneal metastases with oxaliplatin induces biomarkers predicting response to immune checkpoint blockade

Background

Colorectal cancer (CRC) patients with inoperable peritoneal metastases (PM) have a dismal prognosis with limited treatment options. Local treatment of CRC-PM with oxaliplatin is commonly applied, but biomarkers steering patient selection, or informing potentially effective combination therapies are lacking. A novel potentially effective treatment strategy is Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) in which CRC-PM are exposed to cyclic treatment with high concentrations of locally applied oxaliplatin. However, it is unclear whether and how CRC-PM respond to PIPAC.

Methods

Here, we generated a biobank from 20 patients receiving PIPAC with oxaliplatin for CRC-PM. The biobank contains biopsies from 3 PM per patient, repeatedly sampled prior to each treatment cycle, and ascites. Anti-tumor effects were analyzed by shallow single-cell karyotype sequencing (sc-karyoSeq). RNA-sequencing and proteomics were performed to assess changes in gene and protein expression. Immunohistochemistry was performed to assess treatment-induced changes in tissue histology. Ascites was used to assess immunoglobulin content and reactivity.

Results

PIPAC reduced genomic heterogeneity and aneuploidy scores among PIPAC-surviving tumor cells. Furthermore, PIPAC reduced immunosuppressive signals (hypoxia, interleukin-10, transforming growth factor β), and induced an influx of B and T lymphocytes, which organized into metastasis-associated Tertiary Lymphoid Structures (TLS). TLS are biomarkers predicting response to Immune-Checkpoint Inhibitors (ICIs). The T cells residing in PIPAC-induced TLS expressed high levels of the checkpoints PD-1, TIGIT and EBI3. PIPAC also caused the generation of plasma cells producing tumor-reactive antibodies.

Conclusion

PIPAC shows modest anti-tumor activity and induces immune parameters predicting response to ICIs. Patients with inoperable CRC-PM may therefore benefit from PIPAC in combination with ICIs.

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来源期刊

Translational Oncology ONCOLOGY-

CiteScore

8.40

自引率

2.00%

发文量

314

审稿时长

54 days

期刊介绍： Translational Oncology publishes the results of novel research investigations which bridge the laboratory and clinical settings including risk assessment, cellular and molecular characterization, prevention, detection, diagnosis and treatment of human cancers with the overall goal of improving the clinical care of oncology patients. Translational Oncology will publish laboratory studies of novel therapeutic interventions as well as clinical trials which evaluate new treatment paradigms for cancer. Peer reviewed manuscript types include Original Reports, Reviews and Editorials.