Center for Cancer Prevention, Houston Methodist Cancer Center, Houston Methodist Research Institute, Houston, TX, United States.
Cancer Center and Department of Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, WI, United States.
Front Immunol. 2023 Feb 17;14:1036563. doi: 10.3389/fimmu.2023.1036563. eCollection 2023.
Epidermal growth factor receptor (EGFR) mutations occur in about 50% of lung adenocarcinomas in Asia and about 15% in the US. EGFR mutation-specific inhibitors have been developed and made significant contributions to controlling EGFR mutated non-small cell lung cancer. However, resistance frequently develops within 1 to 2 years due to acquired mutations. No effective approaches that target mutant EGFR have been developed to treat relapse following tyrosine kinase inhibitor (TKI) treatment. Vaccination against mutant EGFR is one area of active exploration. In this study, we identified immunogenic epitopes for the common EGFR mutations in humans and formulated a multi-peptide vaccine (E Vax) targeting the EGFR L858R, T790M, and Del19 mutations. The efficacy of the E Vax was evaluated in both syngeneic and genetic engineered EGFR mutation-driven murine lung tumor models with prophylactic settings, where the vaccinations were given before the onset of the tumor induction. The multi-peptide E Vax effectively prevented the onset of EGFR mutation-driven lung tumorigenesis in both syngeneic and genetically engineered mouse models (GEMMs). Flow cytometry and single-cell RNA sequencing were conducted to investigate the impact of E Vax on immune modulation. E Vax significantly enhanced Th1 responses in the tumor microenvironment and decreased suppressive Tregs to enhance anti-tumor efficacy. Our results show that multi-peptide E Vax is effective in preventing common EGFR mutation-driven lung tumorigenesis, and the vaccine elicits broad immune responses that are not limited to anti-tumor Th1 response.
表皮生长因子受体（EGFR）突变发生在约 50%的亚洲肺腺癌和约 15%的美国肺腺癌中。已经开发出了针对 EGFR 突变的特异性抑制剂，这些抑制剂为控制 EGFR 突变的非小细胞肺癌做出了重大贡献。然而，由于获得性突变，耐药性通常在 1 到 2 年内发生。目前还没有针对突变 EGFR 的有效方法来治疗酪氨酸激酶抑制剂（TKI）治疗后的复发。针对突变 EGFR 的疫苗接种是一个积极探索的领域。在这项研究中，我们鉴定了人类常见 EGFR 突变的免疫原性表位，并设计了一种针对 EGFR L858R、T790M 和 Del19 突变的多肽疫苗（E Vax）。我们在具有预防性设置的同源和遗传工程 EGFR 突变驱动的小鼠肺肿瘤模型中评估了 E Vax 的疗效，其中在肿瘤诱导之前给予疫苗接种。多肽 E Vax 有效地预防了同源和遗传工程小鼠模型（GEMMs）中 EGFR 突变驱动的肺肿瘤发生。我们进行了流式细胞术和单细胞 RNA 测序，以研究 E Vax 对免疫调节的影响。E Vax 显著增强了肿瘤微环境中的 Th1 反应，并减少了抑制性 Tregs，从而增强了抗肿瘤疗效。我们的结果表明，多肽 E Vax 可有效预防常见的 EGFR 突变驱动的肺肿瘤发生，并且疫苗引发了广泛的免疫反应，不仅限于抗肿瘤 Th1 反应。
