The success of cancer immunotherapy is largely associated with immunologically hot tumors. Approaches that promote the infiltration of immune cells into tumor beds are urgently needed to transform cold tumors into hot tumors. Oncolytic viruses can transform the tumor microenvironment (TME), resulting in immunologically hot tumors. Cytokines are good candidates for arming oncolytic viruses to enhance their function in this transformation. Here, we used the oncolytic vaccinia virus (oVV) to deliver interleukin-9 (IL-9) into the tumor bed and explored its antitumor effects in colon and lung tumor models. Our data show that IL-9 prolongs viral persistence, which is probably mediated by the up-regulation of IL-10. The vvDD-IL-9 treatment elevated the expression of Th1 chemokines and antitumor factors such as IFN-γ, granzyme B, and perforin. IL-9 expression increased the percentages of CD4+and CD8+T cells in the TME and decreased the percentage of oVV-induced immune suppressive myeloid-derived suppressor cells (MDSC), leading to potent antitumor effects compared with parental virus treatment. The vvDD-IL-9 treatment also increased the percentage of regulatory T cells (Tregs) in the TME and elevated the expression of immune checkpoint molecules such as PD-1, PD-L1, and CTLA-4, but not GITR. The combination therapy of vvDD-IL-9 and the anti-CTLA-4 antibody, but not the anti-GITR antibody, induced systemic tumor-specific antitumor immunity and significantly extended the overall survival of mice, indicating a potential translation of the IL-9-expressing oncolytic virus into a clinical trial to enhance the antitumor effects elicited by an immune checkpoint blockade for cancer immunotherapy.
癌症免疫疗法的成功在很大程度上与免疫学上的"热肿瘤"相关。亟需开发能够促进免疫细胞浸润至肿瘤床的方法，以将"冷肿瘤"转化为"热肿瘤"。溶瘤病毒能够重塑肿瘤微环境，从而形成免疫学上的热肿瘤。细胞因子是增强溶瘤病毒在此转化过程中功能的理想候选武器。本研究采用溶瘤痘苗病毒递送白细胞介素-9至肿瘤床，并在结肠癌和肺癌模型中探究其抗肿瘤效应。数据显示，IL-9通过上调IL-10表达延长了病毒在肿瘤内的持续存在时间。vvDD-IL-9治疗提升了Th1趋化因子及IFN-γ、颗粒酶B、穿孔素等抗肿瘤因子的表达水平。与亲本病毒治疗相比，IL-9表达不仅提高了肿瘤微环境中CD4+和CD8+T细胞比例，同时降低了溶瘤病毒诱导的免疫抑制性髓源性抑制细胞比例，从而产生更强的抗肿瘤效应。值得注意的是，vvDD-IL-9治疗虽增加了调节性T细胞比例，并上调了PD-1、PD-L1和CTLA-4等免疫检查点分子表达（GITR除外），但联合抗CTLA-4抗体（非抗GITR抗体）的治疗方案能诱导全身性肿瘤特异性免疫应答，显著延长小鼠总体生存期。这表明表达IL-9的溶瘤病毒具有临床转化潜力，可通过联合免疫检查点阻断疗法增强癌症免疫治疗的抗肿瘤效果。
肿瘤(癌症)患者之家