Key Laboratory of Proteinand Peptide Pharmaceuticals, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics Chinese Academy of Sciences, Beijing, China.
Guangzhou Laboratory, Guangzhou, China.
J Immunother Cancer. 2023 Mar;11(3). doi: 10.1136/jitc-2022-005925.
Although immune checkpoint blockade (ICB) and adoptive T cell transfer (ACT) therapy have achieved impressive clinical outcomes, majority of patients do not respond to immunotherapy. Tumor-infiltrating T cells, a critical factor to immunotherapy, is dynamically changing. Therefore, a reliable real-time in vivo imaging system for tumor-infiltrating T cells, but not immunohistochemical analyses, will be more valuable to predict response and guide immunotherapy. In this study, we developed a new SPECT/CT imaging probe Tc-sum IL-2 targeting the IL-2Rβ/IL-2Rγ (CD122/CD132) receptor on tumor-infiltrating T cells, and evaluated its application in predicting the immune response to anti-PD-L1 (αPD-L1) therapy as well as tracking infused T cells in ACT therapy.
The binding affinity of the super mutated IL-2 (sum IL-2) in various T cell subtypes was measured. Sum IL-2 was subsequently labeled with Tc through Sortase-A mediated site-specific transpeptidation. SPECT/CT imaging and biodistribution studies of Tc-sum IL-2 were performed in a MC38 mouse model. Wild type IL-2 (IL-2) was used as control in the above studies. Finally, we evaluated Tc-sum IL-2 SPECT/CT for the detection of tumor-infiltrating T cells in the context of αPD-L1 immunotherapy and ACT therapy.
Sum IL-2 preferentially bound to CD8 T cells, especially activated CD8 T cells, while IL-2 showed biased binding to Treg cells. As a result, Tc-sum IL-2 could detect tumor-infiltrating T cells. In the MC38 tumor model, SPECT/CT imaging showed the increased tumor uptake of Tc-sum IL-2 after αPD-L1 treatment, suggesting that the treatment significantly increased tumor-infiltrating T cells, resulting in a correspondingly significant curative effect. In addition, Tc-sum IL-2 SPECT/CT could also track the infiltration of antigen-specific cytotoxic CD8 T cells during ACT therapy.
Tc-sum IL-2 has great clinical potential for non-invasive and specific SPECT/CT imaging of tumor-infiltrating T cells as well as for timely prediction and evaluation of the therapeutic efficacy of ICB and ACT therapy.
尽管免疫检查点阻断（ICB）和过继性 T 细胞转移（ACT）疗法已取得令人瞩目的临床疗效，但大多数患者对免疫疗法无反应。肿瘤浸润 T 细胞是免疫治疗的关键因素，其处于动态变化中。因此，一种可靠的实时体内肿瘤浸润 T 细胞成像系统，而不是免疫组化分析，将更有价值用于预测反应和指导免疫治疗。在这项研究中，我们开发了一种新的 SPECT/CT 成像探针 Tc-sum IL-2，该探针靶向肿瘤浸润 T 细胞上的 IL-2Rβ/IL-2Rγ（CD122/CD132）受体，并评估其在预测抗 PD-L1（αPD-L1）治疗的免疫反应以及在 ACT 治疗中跟踪输注的 T 细胞中的应用。
测量了各种 T 细胞亚型中超突变 IL-2（sum IL-2）的结合亲和力。随后，通过 Sortase-A 介导的位点特异性转肽酶将 sum IL-2 用 Tc 标记。在 MC38 小鼠模型中进行了 Tc-sum IL-2 的 SPECT/CT 成像和生物分布研究。在上述研究中，野生型 IL-2（IL-2）被用作对照。最后，我们评估了 Tc-sum IL-2 SPECT/CT 在 αPD-L1 免疫治疗和 ACT 治疗背景下检测肿瘤浸润 T 细胞的能力。
Sum IL-2 优先与 CD8 T 细胞结合，尤其是激活的 CD8 T 细胞，而 IL-2 偏向于与 Treg 细胞结合。因此，Tc-sum IL-2 可以检测肿瘤浸润 T 细胞。在 MC38 肿瘤模型中，SPECT/CT 成像显示，αPD-L1 治疗后肿瘤对 Tc-sum IL-2 的摄取增加，表明治疗显著增加了肿瘤浸润 T 细胞，从而产生了相应的显著疗效。此外，Tc-sum IL-2 SPECT/CT 还可以在 ACT 治疗期间跟踪抗原特异性细胞毒性 CD8 T 细胞的浸润。
Tc-sum IL-2 具有很大的临床潜力，可用于肿瘤浸润 T 细胞的非侵入性和特异性 SPECT/CT 成像，以及及时预测和评估 ICB 和 ACT 治疗的疗效。
