DataSheet_1_DNA Vaccines Targeting Novel Cancer-Associated Antigens Frequently Expressed in Head and Neck Cancer Enhance the Efficacy of Checkpoint Inhibitor.pdf

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.

不依赖人乳头瘤病毒（HPV）的头颈部鳞状细胞癌（HNSCC）是全球高发的恶性肿瘤。HNSCC患者对抗PD1检查点抑制剂（CPIs）的总缓解率约为16%。影响CPI治疗疗效的核心因素之一为肿瘤浸润T细胞（TILs）的浸润水平，因此将TIL低浸润肿瘤转化为TIL高浸润肿瘤，对改善患者临床结局至关重要。本研究报道一种可促进T细胞浸润、抑制肿瘤生长的新型DNA疫苗。我们在HNSCC患者队列中评估了靶抗原的表达特征及其各自的免疫原性。通过同基因小鼠模型，我们评估了靶向两种新型抗原的DNA疫苗单独使用或联合CPI的抗肿瘤疗效。绝大多数HNSCC患者（43/44）共表达MAGED4B与FJX1，且其对应的四聚体特异性T细胞占比为0.06%~0.12%。在临床前模型中，DNA疫苗可诱导抗原特异性T细胞活化，增加T细胞向肿瘤组织的浸润，但对髓系来源抑制细胞（MDSC）或调节性T细胞无显著影响。该疫苗单独使用或联合抗PD1抗体均可抑制肿瘤生长、改善预后，并可使约75%的受试小鼠实现肿瘤完全清除。HNSCC患者体内预先存在MAGED4B与FJX1反应性T细胞，提示这类广泛表达的抗原具有较高的免疫原性，可通过疫苗接种进一步扩增其特异性T细胞应答。靶向上述抗原的DNA疫苗可诱导强烈的T细胞免疫应答，联合抗PD1抗体可实现优异的肿瘤控制效果，这为以抗原特异性策略惠及更广泛HNSCC患者的联合免疫治疗开辟了新的机遇。