肿瘤相关抗原（TAA）是癌症疫苗的重要靶点。然而，基于 TAA 的疫苗尚未在临床试验中充分发挥其潜力。相比之下，免疫检查点阻断（ICB）已成为一种有效的疗法，可在选定的癌症患者中产生持久的反应。迄今为止，TAAs 和 ICB 益处之间几乎没有普遍关联的报道，大多数研究都集中在癌症中突变率最高的黑色素瘤上。在本研究中，我们基于已知和推定的 TAA 开发了 TAA 负担 (TAB) 算法，并研究了 TAB 与 ICB 福利的关联。对接受抗 PD-L1 治疗的 IMVigor210 尿路上皮癌患者队列的分析表明，高肿瘤突变负荷 (TMB) 削弱了 TAB 与 ICB 益处的关联。此外，TAB 与 ICB 在以免疫细胞 PD-L1 染色阴性为特征的肿瘤中的疗效相关，而免疫细胞上高水平的 PD-L1 染色与 T 细胞耗竭有关。独立临床数据集的验证（包括使用抗 PD1/PD-L1 药物治疗的尿路上皮癌队列和针对头颈癌的新辅助抗 PD1 试验）证实了 TAB 与 ICB 在低 T 细胞耗竭肿瘤中的获益相关的发现。泛癌分析显示，在大多数癌症实体中，T 细胞耗竭较高的肿瘤表现出较低的 TAB 水平，这意味着在已建立抗肿瘤免疫的肿瘤中可能对 TAA 进行免疫编辑。我们的研究挑战了 TAA 与 ICB 反应之间缺乏关联的普遍观念。它还强调了未来研究 TAA 的免疫原性和基于 TAA 的疫苗策略在 T 细胞耗竭水平较低的肿瘤中的必要性。

Tumor-associated antigens (TAAs) are important targets for cancer vaccines. However, TAA-based vaccines have not yet achieved their full potential in clinical trials. In contrast, immune checkpoint blockade (ICB) has emerged as an effective therapy, leading to durable responses in selected cancer patients. To date, few generalizable associations between TAAs and ICB benefit have been reported, with most studies focusing on melanoma that has the highest mutation rate in cancer. In this study, we developed a TAA burden (TAB) algorithm based on known and putative TAAs and investigated the association of TAB with ICB benefit. Analysis of the IMVigor210 patient cohort of urothelial carcinoma treated with anti-PD-L1 revealed that high tumor mutation burden (TMB) weakened the association of TAB with ICB benefit. Furthermore, TAB correlated with ICB efficacy in tumors characterized by negative PD-L1 staining on immune cells, while high levels of PD-L1 staining on immune cells were linked to T-cell exhaustion. Validation across independent clinical datasets-including urothelial carcinoma cohorts treated with anti-PD1/PD-L1 agents and neoadjuvant anti-PD1 trials for head and neck cancers-corroborated the finding that TAB correlates with ICB benefit in tumors with low T-cell exhaustion. Pan-cancer analyses revealed that in most cancer entities, tumors with higher T-cell exhaustion exhibited lower TAB levels, implying possible immunoediting of TAAs in tumors with established antitumor immunity. Our study challenges the prevailing notion of a lack of association between TAAs and ICB response. It also underscores the need for future investigations into the immunogenicity of TAAs and TAA-based vaccine strategies in tumors with low levels of T-cell exhaustion.