Department of Medical Microbiology, Molecular Virology Section, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Int J Cancer. 2014 Feb 15;134(4):859-72. doi: 10.1002/ijc.28418. Epub 2013 Sep 4.
Therapeutic cancer vaccines show promise in preclinical studies, yet their clinical efficacy is limited. Increased recruitment of immune cells into tumors and suppression of the immune suppressive tumor environment are critical components toward effective cancer immunotherapies. Here, we report how local low-dose irradiation, alone or with a therapeutic immunization based on Semliki Forest virus (SFV) against human papillomavirus (HPV)-related cancer, influences these immune mechanisms. We first demonstrated that immunization with SFVeE6,7 or SFVeOVA, replicon particles expressing either HPV16 E6/E7 or ovalbumin, resulted in an antigen-specific migration of CD8+ T cells into HPV- and OVA-specific tumors. Local low-dose tumor irradiation alone resulted in a 2-fold increase of intratumoral CD8+ T cells. When 14 Gy irradiation was combined with immunization, intratumoral numbers of CD8+ T cells increased 10-fold and the number of CD8+ T cells specific for the E7- epitope increased more than 20-fold. Irradiation alone however also increased the number of intratumoral myeloid-derived suppressor cells (MDSCs) 3.5-fold. Importantly, this number did not further increase when combined with immunization. As a result, the ratio of antigen-specific CD8+ T cells and MDSCs in tumors increased up to 85-fold compared to the control. We furthermore demonstrated that following irradiation CCR2 and CCL2, CXCR6 and CCL16, chemokines and ligands involved in tumor homing of immune cells, were significantly up regulated. This study demonstrates that local low-dose tumor irradiation influences the intratumoral immune population induced by SFVeE6,7 immunization by a strong increase in the ratio of antitumoral to immune suppressive cells, thus changing the intratumoral immune balance in favor of antitumor activity.
治疗性癌症疫苗在临床前研究中显示出前景，但它们的临床疗效有限。增加肿瘤内免疫细胞的募集和抑制免疫抑制性肿瘤微环境是有效癌症免疫疗法的关键组成部分。在这里，我们报告了局部低剂量照射，单独或与基于 Semliki Forest 病毒（SFV）的针对人乳头瘤病毒（HPV）相关癌症的治疗性免疫接种，如何影响这些免疫机制。我们首先证明，用 SFVeE6，7 或 SFVeOVA 免疫，表达 HPV16 E6/E7 或卵清蛋白的复制子颗粒，导致 CD8+T 细胞特异性迁移到 HPV 和 OVA 特异性肿瘤中。局部低剂量肿瘤照射本身可使肿瘤内 CD8+T 细胞增加 2 倍。当 14 Gy 照射与免疫接种相结合时，肿瘤内 CD8+T 细胞数量增加 10 倍，针对 E7-表位的 CD8+T 细胞数量增加 20 多倍。然而，单独照射也使肿瘤内髓源抑制细胞（MDSCs）的数量增加了 3.5 倍。重要的是，当与免疫接种结合时，这个数字不会进一步增加。结果，与对照相比，肿瘤中抗原特异性 CD8+T 细胞和 MDSCs 的比值增加了 85 倍。我们还证明，照射后 CCR2 和 CCL2、CXCR6 和 CCL16，参与免疫细胞肿瘤归巢的趋化因子和配体，显著上调。这项研究表明，局部低剂量肿瘤照射通过强烈增加抗肿瘤细胞与免疫抑制细胞的比例，影响 SFVeE6，7 免疫接种诱导的肿瘤内免疫群体，从而改变有利于抗肿瘤活性的肿瘤内免疫平衡。
