Department of Immunohematology and Blood Transfusion, Leiden University Medical Center (LUMC), Leiden, the Netherlands.
Division of Toxicology, Leiden Academic Centre for Drug Research, Leiden University, the Netherlands.
Clin Cancer Res. 2015 Feb 15;21(4):781-94. doi: 10.1158/1078-0432.CCR-14-2142. Epub 2014 Dec 12.
Cancer immunotherapy, such as vaccination, is an increasingly successful treatment modality, but its interaction with chemotherapy remains largely undefined. Therefore, we explored the mechanism of synergy between vaccination with synthetic long peptides (SLP) of human papillomavirus type 16 (HPV16) and cisplatin in a preclinical tumor model for HPV16.
SLP vaccination in this preclinical tumor model allowed the elucidation of novel mechanisms of synergy between chemo- and immunotherapy. By analyzing the tumor immune infiltrate, we focused on the local intratumoral effects of chemotherapy, vaccination, or the combination.
Of several chemotherapeutic agents, cisplatin synergized best with SLP vaccination in tumor eradication, without requirement for the maximum-tolerated dose (MTD). Upon SLP vaccination, tumors were highly infiltrated with HPV-specific, tumor necrosis factor-α (TNFα)- and interferon-γ (IFNγ)-producing T cells. Upon combined treatment, tumor cell proliferation was significantly decreased compared with single treated and untreated tumors. Furthermore, we showed that TNFα strongly enhanced cisplatin-induced apoptotic tumor cell death in a JNK-dependent manner. This is consistent with upregulation of proapoptotic molecules and with enhanced cell death in vivo upon combined SLP vaccination and cisplatin treatment. In vivo neutralization of TNFα significantly reduced the antitumor responses induced by the combined treatment.
Taken together, our data show that peptide vaccination with cisplatin treatment leads to decreased tumor cell proliferation and TNFα-induced enhanced cisplatin-mediated killing of tumor cells, together resulting in superior tumor eradication.
癌症免疫疗法，如疫苗接种，是一种越来越成功的治疗方式，但它与化疗的相互作用在很大程度上仍未得到明确。因此，我们在 HPV16 临床前肿瘤模型中探索了 HPV16 合成长肽 (SLP) 疫苗接种与顺铂联合化疗的协同作用机制。
在这个临床前肿瘤模型中，SLP 疫苗接种允许阐明化疗和免疫治疗协同作用的新机制。通过分析肿瘤免疫浸润，我们专注于化疗、疫苗接种或联合治疗的局部肿瘤内效应。
在几种化疗药物中，顺铂与 SLP 疫苗接种在肿瘤消除方面协同作用最佳，而无需达到最大耐受剂量 (MTD)。在 SLP 疫苗接种后，肿瘤高度浸润 HPV 特异性、肿瘤坏死因子-α (TNFα) 和干扰素-γ (IFNγ) 产生的 T 细胞。联合治疗后，与单独治疗和未治疗的肿瘤相比，肿瘤细胞增殖显著降低。此外，我们表明 TNFα 以依赖 JNK 的方式强烈增强顺铂诱导的肿瘤细胞凋亡。这与体内增强的细胞死亡一致，在体内，联合 SLP 疫苗接种和顺铂治疗后，促凋亡分子的表达上调。体内中和 TNFα 显著降低了联合治疗诱导的抗肿瘤反应。
综上所述，我们的数据表明，顺铂治疗联合肽疫苗接种可导致肿瘤细胞增殖减少和 TNFα 诱导的增强顺铂介导的肿瘤细胞杀伤，从而导致更好的肿瘤消除。
