School of Basic Medical Sciences, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Guangzhou Medical University, Guangzhou, China.
The State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy and Clinical Immunology, Guangzhou, China.
Front Immunol. 2022 Jun 20;13:925217. doi: 10.3389/fimmu.2022.925217. eCollection 2022.
Therapeutic tumor vaccines have become an important breakthrough in the treatment of various solid tumors including lung cancer. Dendritic cells (DCs)-based tumor vaccines targeting tumor-associated antigens (TAAs) play a key role in immunotherapy and immunoprevention. However, the weak immunogenicity of TAAs and low immune response rates are a major challenge faced in the application of therapeutic tumor vaccines. Here, we tested whether targeting an attractive target Mesothelin (MSLN) and PD-L1 immune checkpoint molecule to DCs would elicit therapeutic antitumor cytotoxic T lymphocyte (CTL) response. We generated specific MSLN fragment combined with PD-L1 and GM-CSF peptide immunogen (MSLN-PDL1-GMCSF) based on the novel anti-PD-L1 vaccination strategy we recently developed for the cancer treatment and prevention. We found that DCs loaded with MSLN-PDL1-GMCSF vaccine elicited much stronger endogenous anti-PD-L1 antibody and T cell responses in immunized mice and that antigen specific CTLs had cytolytic activities against tumor cells expressing both MSLN and PD-L1. We demonstrated that vaccination with MSLN-PDL1-GMCSF potently inhibited the tumor growth of MSLN and PD-L1 lung cancer cells, exhibiting a significant therapeutic anti-tumor potential. Furthermore, PD-1 blockade further improved the synergistic antitumor therapeutic efficacy of MSLN-PDL1-GMCSF vaccine in immunized mice. In summary, our data demonstrated for the first time that this PD-L1-containing MSLN therapeutic vaccine can induce persistent anti-PD-L1 antibody and CTL responses, providing an effective immunotherapeutic strategy for lung cancer immunotherapy by combining MSLN-PDL1-GMCSF vaccine and PD-1 blockade.
治疗性肿瘤疫苗已成为治疗各种实体瘤（包括肺癌）的重要突破。针对肿瘤相关抗原（TAA）的树突状细胞（DC）肿瘤疫苗在免疫治疗和免疫预防中发挥着关键作用。然而，TAA 的弱免疫原性和低免疫应答率是治疗性肿瘤疫苗应用中面临的主要挑战。在这里，我们测试了靶向有吸引力的靶标间皮素（MSLN）和 PD-L1 免疫检查点分子的 DC 是否会引发治疗性抗肿瘤细胞毒性 T 淋巴细胞（CTL）反应。我们根据我们最近为癌症治疗和预防开发的新型抗 PD-L1 疫苗策略，生成了基于 MSLN 片段的特异性与 PD-L1 和 GM-CSF 肽免疫原（MSLN-PDL1-GMCSF）。我们发现，负载 MSLN-PDL1-GMCSF 疫苗的 DC 会在免疫小鼠中引发更强的内源性抗 PD-L1 抗体和 T 细胞反应，并且抗原特异性 CTL 对表达 MSLN 和 PD-L1 的肿瘤细胞具有细胞溶解活性。我们证明，用 MSLN-PDL1-GMCSF 疫苗接种可有效抑制 MSLN 和 PD-L1 肺癌细胞的肿瘤生长，表现出显著的治疗性抗肿瘤潜力。此外，PD-1 阻断进一步提高了 MSLN-PDL1-GMCSF 疫苗在免疫小鼠中的协同抗肿瘤治疗效果。总之，我们的数据首次证明，这种包含 PD-L1 的 MSLN 治疗性疫苗可以诱导持续的抗 PD-L1 抗体和 CTL 反应，通过结合 MSLN-PDL1-GMCSF 疫苗和 PD-1 阻断为肺癌免疫治疗提供了一种有效的免疫治疗策略。
