Adoptive cell therapy (ACT) using tumor-specific tumor-infiltrating lymphocytes (TILs) has demonstrated success in patients where tumor-antigen specific TILs can be harvested from the tumor, expanded, and re-infused in combination with a preparatory regimen and IL2. One major issue for non-immunogenic tumors has been that the isolated TILs lack tumor specificity and thus possess limited in vivo therapeutic function. An oncolytic virus (OV) mediates an immunogenic cell death for cancer cells, leading to elicitation and dramatic enhancement of tumor-specific TILs. We hypothesized that the tumor-specific TILs elicited and promoted by an OV would be a great source for ACT for solid cancer. In this study, we show that a local injection of oncolytic poxvirus in MC38 tumor with low immunogenicity in C57BL/6 mice, led to elicitation and accumulation of tumor-specific TILs in the tumor tissue. Our analyses indicated that IL2-armed OV-elicited TILs contain lower quantities of exhausted PD-1^hiTim-3⁺ CD8⁺ T cells and regulatory T cells. The isolated TILs from IL2-expressing OV-treated tumor tissue retained high tumor specificity after expansion ex vivo. These TILs resulted in significant tumor regression and improved survival after adoptive transfer in mice with established MC38 tumor. Our study showcases the feasibility of using an OV to induce tumor-reactive TILs that can be expanded for ACT.

使用肿瘤特异性肿瘤浸润淋巴细胞 (TIL) 的过继细胞疗法 (ACT) 已在患者中取得了成功，可以从肿瘤中收获肿瘤抗原特异性 TIL，进行扩增，并与预备方案和 IL2 结合重新输注。非免疫原性肿瘤的一个主要问题是分离的 TIL 缺乏肿瘤特异性，因此体内治疗功能有限。溶瘤病毒 (OV) 介导癌细胞的免疫原性细胞死亡，从而引发和显着增强肿瘤特异性 TIL。我们假设 OV 引发和促进的肿瘤特异性 TIL 将成为实体癌 ACT 的重要来源。在这项研究中，我们证明，在 C57BL/6 小鼠的 MC38 肿瘤中局部注射具有低免疫原性的溶瘤痘病毒，导致肿瘤组织中肿瘤特异性 TIL 的引发和积累。我们的分析表明，IL2 武装的 OV 引发的 TIL 含​​有较低数量的耗尽的 PD-1 ^hi Tim-3 ⁺ CD8 ⁺ T 细胞和调节性 T 细胞。从表达 IL2 的 OV 处理的肿瘤组织中分离的 TIL 在离体扩增后保留了高肿瘤特异性。这些 TIL 使已形成 MC38 肿瘤的小鼠的肿瘤显着消退，并在过继转移后提高了生存率。我们的研究展示了使用 OV 诱导可扩展用于 ACT 的肿瘤反应性 TIL 的可行性。