UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania.
Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania.
Cancer Immunol Res. 2024 Nov 4;12(11):1589-1602. doi: 10.1158/2326-6066.CIR-23-0932.
Tumor-associated antigens (TAA) 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 patients with cancer. To date, few generalizable associations between TAAs and ICB benefit have been reported, with most studies focusing on melanoma, which 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-PDL1 revealed that high tumor mutation burden weakened the association of TAB with ICB benefit. Furthermore, TAB correlated with ICB efficacy in tumors characterized by negative PDL1 staining on immune cells; however, high levels of PDL1 staining on immune cells were linked to T-cell exhaustion. Validation across independent clinical datasets-including urothelial carcinoma cohorts treated with anti-PD1/PDL1 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.
肿瘤相关抗原 (TAA) 是癌症疫苗的重要靶点。然而，基于 TAA 的疫苗在临床试验中尚未发挥其全部潜力。相比之下，免疫检查点阻断 (ICB) 已成为一种有效的治疗方法，导致部分癌症患者产生持久反应。迄今为止，很少有报道 TAA 与 ICB 获益之间存在普遍关联，大多数研究集中在黑色素瘤上，黑色素瘤是癌症中突变率最高的肿瘤。在这项研究中，我们开发了一种基于已知和推测的 TAA 的 TAA 负担 (TAB) 算法，并研究了 TAB 与 ICB 获益的关联。对接受抗 PD-L1 治疗的尿路上皮癌患者的 IMvigor210 队列进行分析，结果表明高肿瘤突变负担削弱了 TAB 与 ICB 获益的关联。此外，在免疫细胞上 PD-L1 染色阴性的肿瘤中，TAB 与 ICB 疗效相关；然而，免疫细胞上高水平的 PD-L1 染色与 T 细胞衰竭有关。在包括接受抗 PD-1/PD-L1 药物治疗的尿路上皮癌队列和头颈部癌症新辅助抗 PD-1 试验在内的独立临床数据集的验证中，证实了 TAB 与低 T 细胞衰竭肿瘤的 ICB 获益相关。泛癌分析显示，在大多数癌症实体中，T 细胞衰竭较高的肿瘤显示出较低的 TAB 水平，这意味着在具有既定抗肿瘤免疫的肿瘤中，可能存在 TAA 的免疫编辑。我们的研究挑战了 TAA 与 ICB 反应之间缺乏关联的观点。它还强调了需要进一步研究在 T 细胞衰竭水平较低的肿瘤中 TAA 的免疫原性和基于 TAA 的疫苗策略。
