激动型抗体和多聚 TL1A 蛋白靶向 TNFRSF25 共刺激 CD8 T 细胞并抑制肿瘤生长。

Targeting TNFRSF25 by agonistic antibodies and multimeric TL1A proteins co-stimulated CD8 T cells and inhibited tumor growth.

机构信息

Peking University-Tsinghua University-National Institute of Biological Sciences Joint Graduate Program, School of Life Sciences, Tsinghua University, Beijing, China.

National Institute of Biological Sciences, Beijing, China.

出版信息

J Immunother Cancer. 2024 Aug 13;12(8):e008810. doi: 10.1136/jitc-2024-008810.

DOI:10.1136/jitc-2024-008810

PMID:39142717

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11331879/

Abstract

BACKGROUND

Tumor necrosis factor receptor superfamily 25 (TNFRSF25) is a T-cell co-stimulatory receptor. Expression of its ligand, TNF-like cytokine 1A (TL1A), on mouse tumor cells has been shown to promote tumor regression. This study aimed to develop TNFRSF25 agonists (both antibodies (Abs) and TL1A proteins) and to investigate their potential antitumor effects.

METHODS

Anti-mouse TNFRSF25 (mTNFRSF25) Abs and multimeric TL1A proteins were generated as TNFRSF25 agonists. Their agonism was assessed in luciferase reporter and T-cell co-stimulation assays, and their antitumor effects were evaluated in syngeneic mouse tumor models. TNFRSF25 expression within the tumor microenvironment and the effects of an anti-mTNFRSF25 agonistic Ab on tumor-infiltrating T cells were evaluated by flow cytometry. Cell depletion assays were used to identify the immune cell types that contribute to the antitumor effect of the anti-mTNFRSF25 Ab. The Fc gamma receptor (FcγR) dependence of TNFRSF25 agonists was assessed in an T-cell expansion model and a mouse tumor model using Fc variants and FcγR-deficient mice.

RESULTS

TNFRSF25 agonists exhibited antitumor effects in syngeneic mouse tumor models without causing observed side effects. We identified an anti-mTNFRSF25 agonistic Ab, 1A6-m1, which exhibited greater antitumor activity than a higher affinity anti-TNFRSF25 Ab which engages an overlapping epitope with 1A6-m1. 1A6-m1 activated CD8 T cells and antigen-specific T cells, leading to tumor regression; it also induced long-term antitumor immune memory. Although activating TNFRSF25 by 1A6-m1 expanded splenic regulatory T (Treg) cells, it did not influence intratumoral Treg cells. Moreover, 1A6-m1's antitumor effects required the engagement of both inhibitory FcγRIIB and activating FcγRIII. Replacing 1A6-m1's CH1-hinge region with that of human IgG2 (h2) conferred enhanced antitumor effects. Finally, we also generated multimeric human and mouse TL1A fusion proteins as TNFRSF25 agonists, and they co-stimulated CD8 T cells and reduced tumor growth, even in the absence of Fc-FcγR interactions.

CONCLUSION

Our data demonstrates the potential of activating TNFRSF25 by Abs and multimeric TL1A proteins for cancer immunotherapy and provides insights into their development astherapeutics.

摘要

背景

肿瘤坏死因子受体超家族 25（TNFRSF25）是一种 T 细胞共刺激受体。已经证明，其配体 TNF 样细胞因子 1A（TL1A）在小鼠肿瘤细胞上的表达可促进肿瘤消退。本研究旨在开发 TNFRSF25 激动剂（包括抗体（Abs）和 TL1A 蛋白），并研究其潜在的抗肿瘤作用。

方法

生成抗小鼠 TNFRSF25（mTNFRSF25）Abs 和多聚 TL1A 蛋白作为 TNFRSF25 激动剂。在荧光素酶报告和 T 细胞共刺激测定中评估它们的激动作用，并在同种异体小鼠肿瘤模型中评估它们的抗肿瘤作用。通过流式细胞术评估肿瘤微环境中 TNFRSF25 的表达以及抗 mTNFRSF25 激动性 Ab 对肿瘤浸润 T 细胞的影响。细胞耗竭实验用于鉴定导致抗 mTNFRSF25 Ab 抗肿瘤作用的免疫细胞类型。在 T 细胞扩增模型和使用 Fc 变体和 FcγR 缺陷型小鼠的小鼠肿瘤模型中评估 TNFRSF25 激动剂的 Fc 受体（FcγR）依赖性。

结果

TNFRSF25 激动剂在同种异体小鼠肿瘤模型中表现出抗肿瘤作用，而没有观察到明显的副作用。我们鉴定出一种抗 mTNFRSF25 激动性 Ab，1A6-m1，其抗肿瘤活性优于与 1A6-m1 重叠表位的高亲和力抗 TNFRSF25 Ab。1A6-m1 激活 CD8 T 细胞和抗原特异性 T 细胞，导致肿瘤消退；它还诱导长期抗肿瘤免疫记忆。尽管 1A6-m1 通过激活 TNFRSF25 来扩增脾脏调节性 T（Treg）细胞，但它不影响肿瘤内的 Treg 细胞。此外，1A6-m1 的抗肿瘤作用需要结合抑制性 FcγRIIB 和激活 FcγRIII。用人类 IgG2（h2）取代 1A6-m1 的 CH1-hinge 区域赋予了增强的抗肿瘤作用。最后，我们还生成了多聚人源和鼠源 TL1A 融合蛋白作为 TNFRSF25 激动剂，它们共刺激 CD8 T 细胞并减少肿瘤生长，即使在没有 Fc-FcγR 相互作用的情况下也是如此。