Laboratory of Cancer Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland.
Roche Innovation Center Zurich, Schlieren, Switzerland.
J Immunother Cancer. 2020 Jul;8(2). doi: 10.1136/jitc-2019-000238.
The costimulatory receptor 4-1BB (CD137, TNFRSF9) plays an important role in sustaining effective T cell immune responses and is investigated as target for cancer therapy. Systemic 4-1BB directed therapies elicit toxicity or low efficacy, which significantly hampered advancement of 4-1BB-based immunotherapy. Therefore, targeted delivery of 4-1BB agonist to the tumor side is needed for eliciting antitumor efficacy while avoiding systemic toxicity.
We analyzed the immunostimulatory properties of a fibroblast activation protein (FAP)-targeted 4-1BB agonist (FAP-4-1BBL) by assessing tumor-infiltrating lymphocytes' (TIL) activity from patients with non-small cell lung cancer and epithelial ovarian cancer.
Combination treatment with FAP-4-1BBL and T cell receptor stimulation by either anti-CD3 or T cell bispecific antibodies significantly enhanced TIL activation and effector functions, including T cell proliferation, secretion of proinflammatory cytokines and cytotoxicity. Notably, costimulation with FAP-4-1BBL led to de novo secretion of interleukin (IL)-13. This was associated with cytokine-mediated tumor cell apoptosis, which was partially dependent on IL-13 alpha 1/2 receptors and STAT6 phosphorylation.
Our study provides mechanistic insights into T cell stimulation induced by FAP-4-1BBL in primary human tumors and supports the investigation of FAP-4-1BBL compound in early clinical trials.
共刺激受体 4-1BB（CD137，TNFRSF9）在维持有效的 T 细胞免疫反应中发挥重要作用，被研究作为癌症治疗的靶点。全身 4-1BB 定向治疗会引起毒性或低疗效，这极大地阻碍了 4-1BB 为基础的免疫疗法的进展。因此，需要将 4-1BB 激动剂靶向递送至肿瘤部位，以在避免全身毒性的同时发挥抗肿瘤疗效。
我们通过分析非小细胞肺癌和上皮性卵巢癌患者的肿瘤浸润淋巴细胞（TIL）活性，来分析成纤维细胞激活蛋白（FAP）靶向 4-1BB 激动剂（FAP-4-1BBL）的免疫刺激特性。
FAP-4-1BBL 与 T 细胞受体刺激（通过抗 CD3 或 T 细胞双特异性抗体）联合治疗显著增强了 TIL 的激活和效应功能，包括 T 细胞增殖、促炎细胞因子的分泌和细胞毒性。值得注意的是，FAP-4-1BBL 的共刺激导致白细胞介素（IL）-13 的从头分泌。这与细胞因子介导的肿瘤细胞凋亡有关，部分依赖于 IL-13 alpha 1/2 受体和 STAT6 磷酸化。
我们的研究为 FAP-4-1BBL 在原发性人类肿瘤中诱导的 T 细胞刺激提供了机制见解，并支持了 FAP-4-1BBL 化合物在早期临床试验中的研究。
