Che Yuxin, Yang Yang, Suo Jinguo, Chen Chang, Wang Xuelian
Department of Microbiology and Parasitology, College of Basic Medical Science, China Medical University, Shenyang, Liaoning, People's Republic of China.
Department of Dermatology, The First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China.
Cancer Manag Res. 2021 Sep 21;13:7339-7354. doi: 10.2147/CMAR.S329471. eCollection 2021.
The route of administration of a therapeutic tumor vaccine is a critical factor in inducing antitumor activity. In this study, we explored the effects of three vaccination routes (subcutaneous, peritumoral, and intratumoral injection) on antitumor activity induced by a human papillomavirus (HPV) therapeutic vaccine containing HPV16 E7 peptide combined with the adjuvant CpG ODN in established TC-1 grafted tumors.
We used flow cytometry to evaluate splenic and tumor-infiltrating immune cells. We also assessed transcriptional changes in a sequence of immune-related genes in tumors of different treatment groups using quantitative real-time polymerase chain reaction. Immunohistochemistry was used to determine the expression of molecules related to tumor infiltrating immune cells, angiogenesis, and cancer-associated fibroblasts in tumor tissues.
Our results suggested that intratumoral and peritumoral vaccination generated enhanced antitumor activity compared to subcutaneous delivery. In particular, intratumoral vaccination elicited a stronger antitumor effect, with two of the six treated mice being nearly tumor-free at day 28. Three vaccination routes induced increases in splenic CD4+ and/or CD8+ T lymphocytes, and marked decreases in immunosuppressive cells. Peritumoral vaccination increased the tumor-infiltrating CD8+T cells in tumors, while intratumoral vaccination enhanced the tumor-infiltrating CD4+ and CD8+ T lymphocytes, as well as decreased the tumor-infiltrating of immunosuppressive cells, which may result in stronger inhibition of tumor growth and prolonged survival in mice bearing tumors. Furthermore, compared to the subcutaneous route, intratumoral vaccination led to a significant increase in antitumor cytokines and chemokines. In addition, our data showed marked downregulation of MMP-2, MMP-9, VEGF, CD31, and α-SMA in the intratumoral vaccination group, which might contribute to the suppression of tumor invasion, angiogenesis, and metastasis.
Overall, intratumoral vaccination is superior to subcutaneous delivery and has the potential to inhibit tumor growth by improving the tumor microenvironment.
治疗性肿瘤疫苗的给药途径是诱导抗肿瘤活性的关键因素。在本研究中，我们探讨了三种接种途径（皮下、瘤周和瘤内注射）对含有HPV16 E7肽并联合佐剂CpG ODN的人乳头瘤病毒（HPV）治疗性疫苗在已建立的TC-1移植瘤中诱导的抗肿瘤活性的影响。
我们使用流式细胞术评估脾脏和肿瘤浸润免疫细胞。我们还使用定量实时聚合酶链反应评估不同治疗组肿瘤中一系列免疫相关基因的转录变化。免疫组织化学用于确定肿瘤组织中与肿瘤浸润免疫细胞、血管生成和癌症相关成纤维细胞相关分子的表达。
我们的结果表明，与皮下给药相比，瘤内和瘤周接种产生了增强的抗肿瘤活性。特别是，瘤内接种引发了更强的抗肿瘤作用，在第28天，六只接受治疗的小鼠中有两只几乎没有肿瘤。三种接种途径均诱导脾脏CD4+和/或CD8+T淋巴细胞增加，免疫抑制细胞显著减少。瘤周接种增加了肿瘤中肿瘤浸润性CD8+T细胞，而瘤内接种增强了肿瘤浸润性CD4+和CD8+T淋巴细胞，并减少了肿瘤浸润性免疫抑制细胞，这可能导致对荷瘤小鼠肿瘤生长的更强抑制和生存期延长。此外，与皮下途径相比，瘤内接种导致抗肿瘤细胞因子和趋化因子显著增加。此外，我们的数据显示瘤内接种组中MMP-2、MMP-9、VEGF、CD31和α-SMA明显下调，这可能有助于抑制肿瘤侵袭、血管生成和转移。
总体而言，瘤内接种优于皮下给药，并且有潜力通过改善肿瘤微环境来抑制肿瘤生长。
