CD74 is associated with inflamed tumor immune microenvironment and predicts responsiveness to PD-1/CTLA-4 bispecific antibody in patients with solid tumors,Cancer Immunology, Immunotherapy

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CD74 is associated with inflamed tumor immune microenvironment and predicts responsiveness to PD-1/CTLA-4 bispecific antibody in patients with solid tumors
Cancer Immunology, Immunotherapy ( IF 4.6 ) Pub Date : 2024-01-27 , DOI: 10.1007/s00262-023-03604-2
Jianghua Wang ₁ , Xiaoting Li ₁ , Guanxi Xiao ₁ , Jayesh Desai ₂ , Sophia Frentzas _{3,

4} , Zhongmin Maxwell Wang ₅ , Yu Xia ₆ , Baiyong Li ₁

Affiliation

Introduction

Cadonilimab (AK104) is a first-in-class tetravalent bispecific antibody that targets both PD-1 and CTLA-4, showing a manageable safety profile and favorable clinical benefits. This study aimed to identify the biomarkers of clinical response and explore the immune response within the tumor microenvironment upon the AK104 therapy in advanced solid tumors.

Material and methods

Gene expression profiles of paired pre- and post-treatment tumor tissues from twenty-one patients were analyzed. The association of gene expression levels with either clinical efficacy or prognosis was evaluated and subsequently validated with published datasets using log-rank for Kaplan–Meier estimates. Comparative immune profile analyses of tumor microenvironment before and after AK104 treatment were conducted. The visualization of tumor-infiltrating lymphocytes was performed using multiplex immunohistochemistry. The predictive value of CD74 was further validated with protein expression by immunohistochemistry.

Results

Baseline CD74 gene expression was associated with favorable patient outcomes (overall survival [OS], HR = 0.33, 95% CI 0.11–1.03, p = 0.0463), which was further confirmed with the published datasets. Tumors with high CD74 gene expression at baseline were more likely to exhibit an immune-inflamed microenvironment. AK104 efficiently enhanced the infiltration of immune cells in the tumor microenvironment. Additionally, high CD74 protein expression (≥ 10% of the tumor area occupied by CD74 stained immune cells) at baseline was associated with better progressive-free survival (HR = 0.21, 95% CI 0.06–0.68, p = 0.0065) and OS (HR = 0.35, 95% CI 0.12–1.08, p = 0.0615).

Conclusions

Our findings demonstrate that CD74 is a promising predictive biomarker for AK104 therapeutic response in advanced solid tumors.

Trial registration number NCT03261011.

中文翻译：

CD74 与发炎的肿瘤免疫微环境相关，并预测实体瘤患者对 PD-1/CTLA-4 双特异性抗体的反应

介绍

Cadonilimab (AK104) 是一种同类首创的四价双特异性抗体，同时靶向 PD-1 和 CTLA-4，显示出可控的安全性和良好的临床效益。本研究旨在确定临床反应的生物标志物，并探索晚期实体瘤中 AK104 治疗后肿瘤微环境中的免疫反应。

材料与方法

分析了 21 名患者的配对治疗前和治疗后肿瘤组织的基因表达谱。基因表达水平与临床疗效或预后的关联进行了评估，随后使用 Kaplan-Meier 估计的对数秩通过已发表的数据集进行验证。对 AK104 治疗前后的肿瘤微环境进行比较免疫谱分析。使用多重免疫组织化学对肿瘤浸润淋巴细胞进行可视化。 CD74 的预测价值通过免疫组织化学的蛋白表达进一步得到验证。

结果

基线CD74基因表达与良好的患者预后相关（总生存期 [OS]，HR = 0.33，95% CI 0.11–1.03， p = 0.0463），已发表的数据集进一步证实了这一点。基线时CD74基因高表达的肿瘤更有可能表现出免疫炎症的微环境。 AK104有效增强肿瘤微环境中免疫细胞的浸润。此外，基线时高 CD74 蛋白表达（≥ 10% 的肿瘤区域被 CD74 染色的免疫细胞占据）与更好的无进展生存期（HR = 0.21，95% CI 0.06–0.68， p = 0.0065）和 OS 相关。 HR = 0.35，95% CI 0.12–1.08， p = 0.0615）。