Head and Neck Cancer Center, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom.
Cancer Immunology and Immunotherapy Unit, Cancer Research Malaysia, Selangor, Malaysia.
Front Immunol. 2021 Oct 18;12:763086. doi: 10.3389/fimmu.2021.763086. eCollection 2021.
HPV-independent head and neck squamous cell carcinoma (HNSCC) is a common cancer globally. The overall response rate to anti-PD1 checkpoint inhibitors (CPIs) in HNSCC is ~16%. One major factor influencing the effectiveness of CPI is the level of tumor infiltrating T cells (TILs). Converting TILlow tumors to TILhigh tumors is thus critical to improve clinical outcome. Here we describe a novel DNA vaccines to facilitate the T-cell infiltration and control tumor growth. We evaluated the expression of target antigens and their respective immunogenicity in HNSCC patients. The efficacy of DNA vaccines targeting two novel antigens were evaluated with or without CPI using a syngeneic model. Most HNSCC patients (43/44) co-expressed MAGED4B and FJX1 and their respective tetramer-specific T cells were in the range of 0.06-0.12%. In a preclinical model, antigen-specific T cells were induced by DNA vaccines and increased T cell infiltration into the tumor, but not MDSC or regulatory T cells. The vaccines inhibited tumor growth and improved the outcome alone and upon combination with anti-PD1 and resulted in tumor clearance in approximately 75% of mice. Pre-existence of MAGED4B and FJX1-reactive T cells in HNSCC patients suggests that these widely expressed antigens are highly immunogenic and could be further expanded by vaccination. The DNA vaccines targeting these antigens induced robust T cell responses and with the anti-PD1 antibody conferring excellent tumor control. This opens up an opportunity for combination immunotherapy that might benefit a wider population of HNSCC patients in an antigen-specific manner.
HPV 独立型头颈部鳞状细胞癌（HNSCC）是一种全球常见的癌症。抗 PD1 检查点抑制剂（CPIs）在 HNSCC 中的总体反应率约为 16%。影响 CPI 有效性的一个主要因素是肿瘤浸润 T 细胞（TILs）的水平。因此，将 TIL 低肿瘤转化为 TIL 高肿瘤对于改善临床结果至关重要。在这里，我们描述了一种新型 DNA 疫苗，以促进 T 细胞浸润和控制肿瘤生长。我们评估了目标抗原在 HNSCC 患者中的表达及其各自的免疫原性。使用同源模型评估了针对两种新型抗原的 DNA 疫苗在有无 CPI 的情况下的疗效。大多数 HNSCC 患者（43/44）共表达 MAGED4B 和 FJX1，其各自四聚体特异性 T 细胞在 0.06-0.12%范围内。在临床前模型中，DNA 疫苗诱导了抗原特异性 T 细胞，增加了 T 细胞浸润肿瘤，但不会增加 MDSC 或调节性 T 细胞。疫苗单独抑制肿瘤生长并改善预后，与抗 PD1 联合使用可使约 75%的小鼠肿瘤消退。MAGED4B 和 FJX1 反应性 T 细胞在 HNSCC 患者中的预先存在表明这些广泛表达的抗原具有高度免疫原性，可以通过疫苗进一步扩增。针对这些抗原的 DNA 疫苗诱导了强烈的 T 细胞反应，并与抗 PD1 抗体协同作用，可获得出色的肿瘤控制效果。这为组合免疫疗法开辟了机会，可能以抗原特异性方式使更广泛的 HNSCC 患者受益。
