Wu Chia-Jen, Tsai Yi-Ting, Lee I-Jung, Wu Ping-Yi, Lu Long-Sheng, Tsao Wen-Shan, Huang Yi-Jou, Chang Ching-Cheng, Ka Shuk-Man, Tao Mi-Hua
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
Graduate Institute of Microbiology, National Taiwan University, Taipei, Taiwan.
Oncoimmunology. 2018 Jul 23;7(9):e1477459. doi: 10.1080/2162402X.2018.1477459. eCollection 2018.
Immunotherapies have shown promising results in certain cancer patients. For hepatocellular carcinoma (HCC), the multiplicity of an immunotolerant microenvironment within both the tumor, and the liver may limit the efficacy of cancer immunotherapies. Since radiation induces immunogenic cell death and inflammatory reactions within the tumor microenvironment, we hypothesized that a combination therapy of radiation and lasting local immunostimulating agents, achieved by intratumoral injection of an adenoviral vector encoding interleukin 12, may reverse the immunotolerant microenvironment within a well-established orthotopic HCC toward a state favorable for inducing antitumor immunities. Our data showed that radiation and IL-12 combination therapy (RT/IL-12) led to dramatic tumor regression in animals bearing large subcutaneous or orthotopic HCC, induced systemic effect against distant tumor, and significantly prolonged survival. Radiation monotherapy induced tumor regression at early times but afterwards most tumors regained exponential growth, while IL-12 monotherapy only delayed tumor growth. Mechanistic studies revealed that RT/IL-12 increased expression of MHC class II and co-stimulatory molecules CD40 and CD86 on tumor-infiltrating dendritic cells, suggesting an improvement of their antigen presentation activity. RT/IL-12 also significantly reduced accumulation of tumor-infiltrating myeloid-derived suppressor cells (MDSCs) and impaired their suppressive functions by reducing production of reactive oxygen species. Accordingly, tumor-infiltrating CD8 T cells and NK cells were significantly activated toward the antitumor phenotype, as revealed by increased expression of CD107a and TNF-α. Together, our data showed that RT/IL-12 treatment could reset the intratumoral immunotolerant state and stimulate activation of antitumor cellular immunity that is capable of eliminating large established HCC tumors.
免疫疗法在某些癌症患者中已显示出有前景的结果。对于肝细胞癌（HCC），肿瘤和肝脏内免疫耐受微环境的多样性可能会限制癌症免疫疗法的疗效。由于辐射可诱导肿瘤微环境内的免疫原性细胞死亡和炎症反应，我们推测，通过瘤内注射编码白细胞介素12的腺病毒载体实现的辐射与持久局部免疫刺激剂的联合治疗，可能会将已建立的原位HCC内的免疫耐受微环境转变为有利于诱导抗肿瘤免疫的状态。我们的数据表明，辐射与白细胞介素12联合治疗（RT/IL-12）可使患有大型皮下或原位HCC的动物的肿瘤显著消退，诱导对远处肿瘤的全身效应，并显著延长生存期。单纯放疗在早期可诱导肿瘤消退，但之后大多数肿瘤恢复指数生长，而单纯白细胞介素12治疗仅延迟肿瘤生长。机制研究表明，RT/IL-12可增加肿瘤浸润树突状细胞上MHC II类分子以及共刺激分子CD40和CD86的表达，表明其抗原呈递活性得到改善。RT/IL-12还显著减少肿瘤浸润性髓源性抑制细胞（MDSC）的积累，并通过减少活性氧的产生损害其抑制功能。因此，如CD107a和TNF-α表达增加所示，肿瘤浸润性CD8 T细胞和NK细胞被显著激活为抗肿瘤表型。总之，我们的数据表明，RT/IL-12治疗可重置肿瘤内的免疫耐受状态，并刺激抗肿瘤细胞免疫的激活，从而能够消除已形成的大型HCC肿瘤。
