Precision Immunointerception of EGFR-driven Tumorigenesis for Lung Cancer Prevention

Activating mutations in the epidermal growth factor receptor (EGFR) 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 non-small cell lung cancer (NSCLC) with EGFR mutations. 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 inhibitors (TKIs) 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 (Emut Vax) targeting the EGFR L858R, T790M and Del19. The multi-peptide Emut 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 Emut Vax on immune modulation. Emut Vax significantly enhanced the Th1 responses in tumor microenvironment and decreased suppressive Tregs and MDSCs to enhance anti-tumor efficacy. Our results show that multi-peptide Emut 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（epidermal growth factor receptor, EGFR）的激活突变在亚洲肺腺癌病例中占比约50%，在美国约为15%。针对EGFR突变的抑制剂已被开发，并在控制携带EGFR突变的非小细胞肺癌（non-small cell lung cancer, NSCLC）方面取得了显著成效。然而，由于获得性突变，耐药性通常在1至2年内出现。目前尚未开发出针对突变EGFR的有效疗法，用于治疗酪氨酸激酶抑制剂（tyrosine kinase inhibitors, TKIs）治疗后的肿瘤复发。针对突变EGFR的疫苗研发是当前积极探索的领域之一。本研究中，我们鉴定了人类常见EGFR突变的免疫原性表位，并研发了针对EGFR L858R、T790M与Del19突变的多肽疫苗（Emut Vax）。该多肽疫苗Emut Vax可在同基因小鼠模型与基因工程小鼠模型（genetically engineered mouse models, GEMMs）中有效阻断EGFR突变驱动的肺肿瘤发生。我们通过流式细胞术与单细胞RNA测序，探究了Emut Vax对免疫调控的影响。结果显示，Emut Vax可显著增强肿瘤微环境中的Th1型免疫应答，并降低抑制性调节性T细胞（regulatory T cells, Tregs）与髓系来源抑制细胞（myeloid-derived suppressor cells, MDSCs）的水平，从而提升抗肿瘤疗效。本研究结果表明，多肽疫苗Emut Vax可有效预防常见EGFR突变驱动的肺肿瘤发生，且该疫苗可诱导广泛的免疫应答，不限于抗肿瘤Th1型免疫反应。