PO.TB10.02 · 肿瘤生物学

结直肠癌原发肿瘤与配对肝转移灶中的免疫-血管特征

Immune-vascular profiles in primary tumors and paired liver metastases of colorectal cancer

编号 6119 展板 10 时间 4/21 02:00–05:00 区域 Section 28 主讲 Alfonso MARTIN-BERNABE, PhD

分会场 Metastasis and Organ-Specific Microenvironmental Evolution

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作者与单位 Authors & Affiliations

Alfonso Martín-Bernabé¹, Tove Bekkhus², Elisabet Rodríguez-Tomàs², Reetta Peltonen³, Pauliina Reijonen³, Emerik Osterlund⁴, Caj Haglund⁵, Jaana Hagström³, Helena Isoniemi³, Bengt Glimelius¹, Tobias Sjöblom¹, Arne Östman², Ari Ristimäki³, Teijo Pellinen⁵, Pia Osterlund⁶

¹Uppsala University, Uppsala, Sweden,²Karolinska Institutet, Stockholm, Sweden,³Helsinki University Hospital and University of Helsinki, Helsinki, Finland,⁴The University of Texas MD Anderson Cancer Center, Houston, TX,⁵University of Helsinki, Helsinki, Finland,⁶Tampere University Hospital and Karolinska Institutet, Tampere/Stockholm, Finland

摘要 Abstract

中文摘要

背景：肿瘤微环境的免疫和血管特征影响结直肠癌肝转移（CRLMs）患者的预后。然而，对原发性结直肠肿瘤及其匹配CRLMs之间这些特征及其相互作用的比较分析，以及它们由治疗驱动的重塑，仍很有限。方法：我们分析了来自50例匹配原发肿瘤和CRLM（15例未治疗，35例在肝切除前接受了细胞毒性药物±VEGF-/EGFR-靶向药物的新辅助治疗）的每个肿瘤1-3个TMA芯（1 mm）。我们使用多重免疫荧光对T细胞密度（CD3、CD4、CD8、PD1、FOXP3、TIM3、Ki67）、血管（claudin-5）和血管周（PV）亚群（alphaSMA、PDGFRbeta）比例进行定量。统计分析包括非参数检验（Wilcoxon、Mann-Whitney、Spearman）和用于一致性的组内相关系数（ICC）。结果：未治疗的配对原发肿瘤与CRLMs的比较发现，CRLMs中CD3+CD8+Ki67+、CD3+CD4+Ki67+、CD3+CD4+FOXP3+和CD3+CD8+PD1+细胞的密度显著较低（所有p ≤ 0.006）。在血管方面，CRLMs表现出较低比例的alphaSMA+PDGFRbeta+ PV亚群（p=0.001）、较高比例的alphaSMA+PDGFRbeta- PV亚群（p<0.001）以及增加的血管密度（p=0.01）。对比未治疗与治疗CRLM的分析显示，治疗CRLM中血管尺寸减小（p=0.002）。还进行了具有潜在功能意义的免疫-血管共现模式分析。在未治疗的原发肿瘤中，alphaSMA-PDGFRbeta+ PV亚群与CD3+CD8+FOXP3+（r=0.66, p=0.008）、CD3+CD8+Ki67+（r=0.61, p=0.016）和CD3+CD4+PD1+（r=0.59, p=0.002）细胞密度呈正相关。相比之下，在未治疗的CRLMs中，alphaSMA+PDGFRbeta+ PV亚群与CD3+CD4+Ki67+（r=0.56, p=0.03）和CD3+CD4+PD1+（r=0.62, p=0.013）细胞密度相关。此外，在CRLMs中，较大的血管尺寸与较高的CD3+CD4+细胞密度独特地相关（r=0.54, p=0.04）。接受过治疗的CRLMs缺乏未治疗CRLMs的这些关联，反而显示出新的关联，如alphaSMA-PDGFRbeta+ PV亚群与CD3+CD8+Ki67+细胞（r=0.40, p=0.018）。最后，对未治疗原发肿瘤和CRLM中标志物状态的病例内一致性ICC分析显示，血管指标在患者内部更为稳定（alphaSMA-PDGFRbeta+ PV亚群ICC=0.60；血管尺寸ICC=0.36），而T细胞密度则不然（平均ICC=0.02）。结论：这些探索性分析表明，与原发肿瘤相比，CRLM的特征是较低的免疫细胞密度和不同的PV基质。治疗对CRLM血管特征的影响似乎强于对免疫特征的影响。此外，免疫-血管共现模式具有部位特异性并受治疗调控。总的来说，这些初步结果鉴定出免疫-血管特征，值得就其生物标志物和药物靶点潜力进行进一步探索。

查看英文原文 English abstract

Background: The immune and vascular features of the tumor microenvironment influence outcomes of patients with colorectal cancer liver metastases (CRLMs). However, comparative analyses of these features, and their interactions, between primary colorectal tumors and their matched CRLMs, as well as their treatment-driven remodeling are limited. Methods: We analyzed 1-3 TMA cores per tumor (1 mm) from 50 matched primary tumors and CRLM (15 untreated, 35 neoadjuvant-treated with cytotoxic ±VEGF-/EGFR-targeted agents before liver resection). We used multiplex immunofluorescence to quantify T-cell densities (CD3, CD4, CD8, PD1, FOXP3, TIM3, Ki67), vessels (claudin-5) and perivascular (PV) subset (alphaSMA, PDGFRbeta) fractions. Statistical analyses included non-parametric tests (Wilcoxon, Mann-Whitney, Spearman) and Intraclass Correlation Coefficient (ICC) for concordance. Results: Comparisons of untreated paired primary tumors and CRLMs identified significantly lower densities of CD3+CD8+Ki67+, CD3+CD4+Ki67+, CD3+CD4+FOXP3+, and CD3+CD8+PD1+ cells (all p ≤ 0.006) in CRLMs. Regarding vessels, CRLMs showed a lower fraction of alphaSMA+PDGFRbeta+ PV subset (p=0.001), higher fraction of alphaSMA+PDGFRbeta- PV subset (p<0.001), and increased vessel density (p=0.01). Analyses contrasting untreated and treated CRLM showed reduced vessel size (p=0.002) in treated CRLM. Analysis of immune-vascular co-occurrence patterns of potential functional significance was also performed. In untreated primaries, the alphaSMA-PDGFRbeta+ PV subset correlated positively with densities of CD3+CD8+FOXP3+ (r=0.66, p=0.008), CD3+CD8+Ki67+ (r=0.61, p=0.016), and CD3+CD4+PD1+ (r=0.59, p=0.002) cells. In contrast, in untreated CRLMs, the alphaSMA+PDGFRbeta+ PV subset correlated with CD3+CD4+Ki67+ (r=0.56, p=0.03) and CD3+CD4+PD1+ (r=0.62, p=0.013) cell densities. Furthermore, in CRLMs, larger vessel size was uniquely associated with higher CD3+CD4+ cell density (r=0.54, p=0.04). Treatment-exposed CRLMs lacked the associations of untreated CRLMs and instead displayed new associations such as alphaSMA-PDGFRbeta+ PV subset and CD3+CD8+Ki67+ cells (r=0.40, p=0.018). Finally, ICC analyses of inside-case concordance regarding marker status in untreated primary, and CRLM showed that vascular metrics were more stable within patients (alphaSMA-PDGFRbeta+ PV subset ICC=0.60; vessel size ICC=0.36), than T-cell densities (mean ICC=0.02). Conclusion: These exploratory analyses indicate that CRLM is characterized by lower immune cell densities and a different PV stroma compared to primary tumors. Treatment appears to have a stronger impact on CRLM vessel features than on immune features. Furthermore, immune-vascular co-occurrence patterns are site specific and modulated by treatment. Collectively, these preliminary results identify immune-vascular features for further exploration regarding biomarker and drug target potential.

利益披露 Disclosure

A. Martín-Bernabé, None.. T. Bekkhus, None.. E. Rodríguez-Tomàs, None.. R. Peltonen, None.. P. Reijonen, None.. E. Osterlund, None.. C. Haglund, None.. J. Hagström, None.. H. Isoniemi, None.. B. Glimelius, None.. T. Sjöblom, None.. A. Östman, None.. A. Ristimäki, None.. P. Osterlund, None.

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