Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Unit 1950, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.
MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, 77030, USA.
Cancer Immunol Immunother. 2022 Jul;71(7):1611-1623. doi: 10.1007/s00262-021-03099-9. Epub 2021 Nov 3.
We tested the concept that host preexisting influenza A virus immunity can be redirected to inhibit tumor growth and metastasis through systemic administration of influenza A virus-related peptides to targeted tumors. Mice infected with influenza A virus strain A/Puerto Rico/8/34 (PR8) were used as a model of a host with preexisting viral immunity. The extent to which preexisting influenza A immunity in PR8-immunized mice can be redirected to inhibit tumor growth and metastasis was first examined by ectopic expression of influenza A nucleoprotein (NP) and hemagglutinin (HA) in syngeneic mammary tumor cells via lentiviral transduction. Then, the feasibility of implementing this strategy using a systemic therapy approach was assessed by systemic delivery of major histocompatibility complex class I (MHC-I)-compatible peptides to targeted mammary tumors overexpressing human epidermal growth factor receptor-2 (HER2) in mice using a novel HER2-targeting single-lipid nanoparticle (SLNP). Our results show that preexisting influenza A immunity in PR8-immunized mice could be quickly redirected to syngeneic tumors expressing influenza A NP and HA, leading to strong inhibition of tumor growth and metastasis and improvement of survival compared to the findings in antigen-naïve control mice. MHC-I-compatible peptides could be delivered to targeted mammary tumors in mice using the HER2-targeting SLNP for antigen presentation, which subsequently redirected preexisting influenza A immunity to the tumors to exert antitumor activities. In conclusion, preexisting influenza A immunity can be repurposed for cancer immunotherapy through systemic delivery of influenza A-related peptides to targeted tumors. Further development of the strategy for clinical translation is warranted.
我们测试了这样一个概念，即通过向靶向肿瘤全身给予流感病毒相关肽，可以将宿主预先存在的甲型流感病毒免疫重新定向以抑制肿瘤生长和转移。我们使用感染甲型流感病毒株 A/Puerto Rico/8/34（PR8）的小鼠作为具有预先存在病毒免疫的宿主模型。首先通过慢病毒转导在同基因乳腺肿瘤细胞中外源表达甲型流感核蛋白（NP）和血凝素（HA），来检测 PR8 免疫小鼠预先存在的甲型流感免疫可以在多大程度上被重新定向以抑制肿瘤生长和转移。然后，通过使用新型 HER2 靶向单脂质纳米颗粒（SLNP）将 MHC-I 相容肽全身递送至过表达人表皮生长因子受体-2（HER2）的靶向乳腺肿瘤，评估了使用全身治疗方法实施该策略的可行性。我们的结果表明，PR8 免疫小鼠的预先存在的甲型流感免疫可以迅速被重新定向到表达甲型流感 NP 和 HA 的同基因肿瘤，与抗原-naive 对照小鼠相比，肿瘤生长和转移受到强烈抑制，生存时间得到改善。可以使用 HER2 靶向 SLNP 将 MHC-I 相容肽递送至小鼠中的靶向乳腺肿瘤，用于抗原呈递，随后将预先存在的甲型流感免疫重新定向至肿瘤以发挥抗肿瘤活性。总之，通过向靶向肿瘤全身给予流感相关肽，可以重新利用预先存在的甲型流感免疫用于癌症免疫治疗。需要进一步开发该策略以进行临床转化。
