Department of Genetics and Microbiology, Faculty of Science, Charles University, BIOCEV, 25250 Vestec, Czech Republic.
Int J Mol Sci. 2018 Nov 21;19(11):3693. doi: 10.3390/ijms19113693.
Combined immunotherapy constitutes a novel, advanced strategy in cancer treatment. In this study, we investigated immunotherapy in the mouse TC-1/A9 model of human papillomavirus type 16 (HPV16)-associated tumors characterized by major histocompatibility complex class I (MHC-I) downregulation. We found that the induction of a significant anti-tumor response required a combination of DNA vaccination with the administration of an adjuvant, either the synthetic oligodeoxynucleotide ODN1826, carrying immunostimulatory CpG motifs, or α-galactosylceramide (α-GalCer). The most profound anti-tumor effect was achieved when these adjuvants were applied in a mix with a one-week delay relative to DNA immunization. Combined immunotherapy induced tumor infiltration with various subsets of immune cells contributing to tumor regression, of which cluster of differentiation (CD) 8⁺ T cells were the predominant subpopulation. In contrast, the numbers of tumor-associated macrophages (TAMs) were not markedly increased after immunotherapy but in vivo and in vitro results showed that they could be repolarized to an anti-tumor M1 phenotype. A blockade of T cell immunoglobulin and mucin-domain containing-3 (Tim-3) immune checkpoint had a negligible effect on anti-tumor immunity and TAMs repolarization. Our results demonstrate a benefit of combined immunotherapy comprising the activation of both adaptive and innate immunity in the treatment of tumors with reduced MHC-I expression.
联合免疫疗法是癌症治疗的一种新颖而先进的策略。在这项研究中，我们研究了在人乳头瘤病毒 16（HPV16）相关肿瘤的 TC-1/A9 小鼠模型中进行的免疫疗法，该模型的特点是主要组织相容性复合体 I 类（MHC-I）下调。我们发现，诱导显著的抗肿瘤反应需要将 DNA 疫苗接种与佐剂的给药相结合，佐剂可以是携带免疫刺激性 CpG 基序的合成寡脱氧核苷酸 ODN1826，也可以是α-半乳糖神经酰胺（α-GalCer）。当这些佐剂在 DNA 免疫接种后一周延迟时混合使用时，会产生最显著的抗肿瘤作用。联合免疫疗法诱导了各种免疫细胞亚群浸润肿瘤，有助于肿瘤消退，其中 CD8+T 细胞是主要亚群。相比之下，免疫疗法后肿瘤相关巨噬细胞（TAMs）的数量没有明显增加，但体内和体外结果表明它们可以被重新极化到抗肿瘤的 M1 表型。阻断 T 细胞免疫球蛋白和粘蛋白结构域包含 3（Tim-3）免疫检查点对抗肿瘤免疫和 TAMs 极化几乎没有影响。我们的研究结果表明，联合免疫疗法可以同时激活适应性和固有免疫，对 MHC-I 表达降低的肿瘤具有治疗益处。
