转移性淋巴结靶向 CTLA4 阻断：一种潜在的干预措施，可减少 ICI 诱导的肺炎，同时有效控制局部和远处转移。

Metastatic lymph node targeted CTLA4 blockade: a potent intervention for local and distant metastases with minimal ICI-induced pneumonia.

机构信息

Laboratory of Biomedical Engineering for Cancer, Graduate School of Biomedical Engineering, Tohoku University, 4-1 Seiryo, Aoba, Sendai, Miyagi, 980-8575, Japan.

Biomedical Engineering Cancer Research Center, Graduate School of Biomedical Engineering, Tohoku University, 4-1 Seiryo, Aoba, Sendai, Miyagi, 980-8575, Japan.

出版信息

J Exp Clin Cancer Res. 2023 Jun 1;42(1):132. doi: 10.1186/s13046-023-02645-w.

DOI:10.1186/s13046-023-02645-w

PMID:37259163

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10233978/

Abstract

BACKGROUND

Immune checkpoint blockade (ICB) elicits a strong and durable therapeutic response, but its application is limited by disparate responses and its associated immune-related adverse events (irAEs). Previously, in a murine model of lymph node (LN) metastasis, we showed that intranodal administration of chemotherapeutic agents using a lymphatic drug delivery system (LDDS) elicits stronger therapeutic responses in comparison to systemic drug delivery approaches, while minimizing systemic toxicity, due to its improved pharmacokinetic profile at the intended site. Importantly, the LN is a reservoir of immunotherapeutic targets. We therefore hypothesized that metastatic LN-targeted ICB can amplify anti-tumor response and uncouple it from ICB-induced irAEs.

METHODS

To test our hypothesis, models of LN and distant metastases were established with luciferase expressing LM8 cells in MXH10/Mo-lpr/lpr mice, a recombinant inbred strain of mice capable of recapitulating ICB-induced interstitial pneumonia. This model was used to interrogate ICB-associated therapeutic response and immune related adverse events (irAEs) by in vivo imaging, high-frequency ultrasound imaging and histopathology. qPCR and flowcytometry were utilized to uncover the mediators of anti-tumor immunity.

RESULTS

Tumor-bearing LN (tbLN)-directed CTLA4 blockade generated robust anti-tumor response against local and systemic metastases, thereby improving survival. The anti-tumor effects were accompanied by an upregulation of effector CD8T cells in the tumor-microenvironment and periphery. In comparison, non-specific CTLA4 blockade was found to elicit weaker anti-tumor effect and exacerbated ICI-induced irAEs, especially interstitial pneumonia. Together these data highlight the importance of tbLN-targeted checkpoint blockade for efficacious response.

CONCLUSIONS

Intranodal delivery of immune checkpoint inhibitors to metastatic LN can potentiate therapeutic response while minimizing irAEs stemming from systemic lowering of immune activation threshold.

摘要

背景

免疫检查点阻断（ICB）引发强烈且持久的治疗反应，但由于不同的反应和相关的免疫相关不良事件（irAEs），其应用受到限制。以前，在淋巴结（LN）转移的小鼠模型中，我们表明，使用淋巴药物递送系统（LDDS）在淋巴结内给予化疗药物比全身药物递送方法引发更强的治疗反应，同时最大限度地减少全身毒性，因为其在预期部位的药代动力学特征得到改善。重要的是，LN 是免疫治疗靶点的储库。因此，我们假设转移性 LN 靶向 ICB 可以放大抗肿瘤反应，并将其与 ICB 诱导的 irAEs 脱钩。

方法

为了验证我们的假设，我们在能够重现 ICB 诱导的间质性肺炎的重组近交系 MXH10/Mo-lpr/lpr 小鼠中建立了带有荧光素酶表达的 LM8 细胞的 LN 和远处转移模型。该模型用于通过体内成像、高频超声成像和组织病理学来研究 ICB 相关的治疗反应和免疫相关不良事件（irAEs）。qPCR 和流式细胞术用于揭示抗肿瘤免疫的介质。

结果

肿瘤负荷 LN（tbLN）导向的 CTLA4 阻断针对局部和全身转移产生了强大的抗肿瘤反应，从而提高了生存率。抗肿瘤作用伴随着肿瘤微环境和外周效应性 CD8T 细胞的上调。相比之下，非特异性 CTLA4 阻断被发现引发较弱的抗肿瘤作用，并加剧了 ICI 诱导的 irAEs，特别是间质性肺炎。这些数据共同强调了 tbLN 靶向检查点阻断对于有效反应的重要性。