Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands.
Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands.
J Immunother Cancer. 2022 Jul;10(7). doi: 10.1136/jitc-2021-004464.
Many solid tumors do not respond to immunotherapy due to their immunologically cold tumor microenvironment (TME). We and others found that oncolytic viruses (OVs), including reovirus type 3 Dearing, can enhance the efficacy of immunotherapy by recruiting CD8 T cells to the TME. A significant part of the incoming CD8 T cells is directed toward reovirus itself, which may be detrimental to the efficacy of OVs. However, here we aim to exploit these incoming virus-specific T cells as anticancer effector cells.
We performed an in-depth characterization of the reovirus-induced T-cell response in immune-competent mice bearing pancreatic KPC3 tumors. The immunodominant CD8 T-cell epitope of reovirus was identified using epitope prediction algorithms and peptide arrays, and the quantity and quality of reovirus-specific T cells after reovirus administration were assessed using high-dimensional flow cytometry. A synthetic long peptide (SLP)-based vaccination strategy was designed to enhance the intratumoral frequency of reovirus-specific CD8 T cells.
Reovirus administration did not induce tumor-specific T cells but rather induced high frequencies of reovirus-specific CD8 T cells directed to the immunodominant epitope. Priming of reovirus-specific T cells required a low-frequent population of cross-presenting dendritic cells which was absent in mice. While intratumoral and intravenous reovirus administration induced equal systemic frequencies of reovirus-specific T cells, reovirus-specific T cells were highly enriched in the TME exclusively after intratumoral administration. Here, they displayed characteristics of potent effector cells with high expression of KLRG1, suggesting they may be responsive against local reovirus-infected cells. To exploit these reovirus-specific T cells as anticancer effector cells, we designed an SLP-based vaccination strategy to induce a strong T-cell response before virotherapy. These high frequencies of circulating reovirus-specific T cells were reactivated on intratumoral reovirus administration and significantly delayed tumor growth.
These findings provide proof of concept that OV-specific T cells, despite not being tumor-specific, can be exploited as potent effector cells for anticancer treatment when primed before virotherapy. This is an attractive strategy for low-immunogenic tumors lacking tumor-specific T cells.
许多实体瘤对免疫疗法没有反应，因为其肿瘤微环境（TME）具有免疫冷性。我们和其他人发现，溶瘤病毒（OVs），包括 reovirus type 3 Dearing，可以通过将 CD8 T 细胞募集到 TME 中来增强免疫疗法的疗效。传入的 CD8 T 细胞的很大一部分针对的是 reovirus 本身，这可能对 OVs 的疗效有害。然而，在这里，我们旨在利用这些传入的病毒特异性 T 细胞作为抗癌效应细胞。
我们在携带胰腺 KPC3 肿瘤的免疫功能正常的小鼠中对 reovirus 诱导的 T 细胞反应进行了深入表征。使用表位预测算法和肽阵列鉴定了 reovirus 的免疫优势 CD8 T 细胞表位，并用高维流式细胞术评估了 reovirus 给药后 reovirus 特异性 T 细胞的数量和质量。设计了基于合成长肽（SLP）的疫苗接种策略来增强肿瘤内 reovirus 特异性 CD8 T 细胞的频率。
reovirus 给药不会诱导肿瘤特异性 T 细胞，而是诱导针对免疫显性表位的高频率 reovirus 特异性 CD8 T 细胞。reovirus 特异性 T 细胞的启动需要低频率的交叉呈递树突状细胞，而 小鼠中不存在这种细胞。虽然肿瘤内和静脉内 reovirus 给药诱导相等的系统 reovirus 特异性 T 细胞频率，但仅在肿瘤内给药后，reovirus 特异性 T 细胞在 TME 中高度富集。在这里，它们表现出具有高 KLRG1 表达的有效效应细胞的特征，表明它们可能对局部 reovirus 感染的细胞有反应。为了利用这些 reovirus 特异性 T 细胞作为抗癌效应细胞，我们设计了一种基于 SLP 的疫苗接种策略，在病毒治疗前诱导强烈的 T 细胞反应。这些循环中的高频率 reovirus 特异性 T 细胞在肿瘤内 reovirus 给药时被重新激活，并显著延迟肿瘤生长。
这些发现为概念证明提供了依据，即尽管 OV 特异性 T 细胞不是肿瘤特异性的，但在病毒治疗前被预先激活时，它们可以作为有效的抗癌治疗效应细胞。对于缺乏肿瘤特异性 T 细胞的低免疫原性肿瘤，这是一种有吸引力的策略。
