CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：TNFR2 blockade promotes antitumoral immune response in PDAC by targeting activated Treg and reducing T cell exhaustion.
TNFR2 blockade promotes antitumoral immune response in PDAC by targeting activated Treg and reducing T cell exhaustion.
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我们的数据表明，将 CD40 激动剂与 TNFR2 拮抗剂联合使用是 PDAC 患者一种有前景的治疗策略。
胰腺导管腺癌（PDAC）是最具侵袭性的癌症之一，对标准化疗和免疫疗法高度耐药。表达肿瘤坏死因子受体2（TNFR2）的调节性T细胞（Treg）可促进PDAC免疫抑制。Treg浸润与PDAC患者生存较差和肿瘤进展相关。我们假设，使用阻断性单克隆抗体（mAb）抑制TNFR2，可改变PDAC中Treg与效应T细胞的平衡，从而增强抗肿瘤应答。
为支持该假设，我们首先基于公开的单细胞分析数据，描述24例PDAC患者中的TNFR2表达情况。在PDAC原位和免疫功能完整小鼠模型中，我们还通过免疫细胞分选和单细胞分析描述PDAC免疫环境。评估抗TNFR2 mAb治疗前后免疫环境的变化，以及其对肿瘤进展的影响。
PDAC患者Treg、髓系细胞和内皮细胞中的TNFR2表达升高，而肿瘤细胞中的表达较低。通过流式细胞术和单细胞RNA测序分析，我们在原位小鼠模型中鉴定出两类Treg：静息型和活化型。抗TNFR2 mAb选择性靶向活化的肿瘤浸润Treg，降低CD8+ T细胞中的耗竭标志物。然而，单用抗TNFR2治疗活化CD8+ T细胞的效果有限，且仅轻度降低肿瘤生长。抗TNFR2 mAb与激动性抗CD40 mAb联合，能更强地活化T细胞、抑制肿瘤生长，并改善PDAC荷瘤小鼠生存和免疫记忆。
我们的数据提示，联合使用CD40激动剂和TNFR2拮抗剂，是治疗PDAC患者的一种有前景的策略。
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, highly resistant to standard chemotherapy and immunotherapy. Regulatory T cells (Tregs) expressing tumor necrosis factor receptor 2 (TNFR2) contribute to immunosuppression in PDAC. Treg infiltration correlates with poor survival and tumor progression in patients with PDAC. We hypothesized that TNFR2 inhibition using a blocking monoclonal antibody (mAb) could shift the Treg-effector T cell balance in PDAC, thus enhancing antitumoral responses. METHOD: To support this hypothesis, we first described TNFR2 expression in a cohort of 24 patients with PDAC from publicly available single-cell analysis data. In orthotopic and immunocompetent mouse models of PDAC, we also described the immune environment of PDAC after immune cell sorting and single-cell analysis. The modifications of the immune environment before and after anti-TNFR2 mAb treatment were evaluated as well as the effect on tumor progression.
Patients with PDAC exhibited elevated TNFR2 expression in Treg, myeloid cells and endothelial cells and lower level in tumor cells. By flow cytometry and single-cell RNA-seq analysis, we identified two Treg populations in orthotopic mouse models: Resting and activated Tregs. The anti-TNFR2 mAb selectively targeted activated tumor-infiltrating Tregs, reducing T cell exhaustion markers in CD8 + T cells. However, anti-TNFR2 treatment alone had limited efficacy in activating CD8 + T cells and only slightly reduced the tumor growth. The combination of the anti-TNFR2 mAb with agonistic anti-CD40 mAb promoted stronger T cell activation, tumor growth inhibition, and improved survival and immunological memory in PDAC-bearing mice.
Our data suggest that combining a CD40 agonist with a TNFR2 antagonist represents a promising therapeutic strategy for patients with PDAC.
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