T 细胞识别肿瘤中多种类型的抗原，包括异常表达的非突变蛋白（因此与正常组织共享，称为自身/共享抗原（SSA））以及突变蛋白或致癌病毒蛋白（称为自身/共享抗原）。作为肿瘤特异性抗原（TSA）。免疫检查点阻断 (ICB) 等免疫疗法可以激活 T 细胞针对 TSA 的反应，从而控制肿瘤，也可以激活针对 SSA 的 T 细胞反应，从而导致免疫相关不良事件 (IrAE)。为了提高抗 TSA 免疫力，同时限制抗 SSA 自身反应性，我们需要了解肿瘤特异性 CD8 T 细胞 (TST) 和 SSA 特异性 CD8 T (SST) 细胞在肿瘤发生过程中如何响应同源抗原而分化。因此，我们开发了一种遗传癌症小鼠模型，可以在肝癌发展过程中纵向追踪 TST 和 SST 分化。我们发现，随着时间的推移，TST 和 SST 都失去了效应功能，但 TST 长期持续存在，并具有功能障碍/耗尽表型（包括 PD1、CD39 和 TOX 的表达），而 SST 过早退出细胞周期并从肝脏病变中消失。然而，SST 在脾脏中持续存在功能失调的 TCF1 PD1- 状态：无法产生效应细胞因子或响应针对 PD1 或 PDL1 的 ICB 进行增殖。因此，我们的研究确定了对 SSA 反应的 T 细胞占据的功能失调的 T 细胞状态：缺乏效应器功能的 TCF1 PD1 状态，证明肿瘤抗原的类型/特异性可能决定肿瘤反应性 T 细胞的分化。

T cells recognize several types of antigens in tumors, including aberrantly expressed, non-mutated proteins, which are therefore shared with normal tissue and referred to as self/shared-antigens (SSA), and mutated proteins or oncogenic viral proteins, which are referred to as tumor-specific antigens (TSA). Immunotherapies such as immune checkpoint blockade (ICB) can activate T-cell responses against TSA, leading to tumor control, and also against SSA, causing immune-related adverse events (IrAE). To improve anti-TSA immunity while limiting anti-SSA autoreactivity, we need to understand how tumor-specific CD8+ T cells (TST) and SSA-specific CD8+ T (SST) cells differentiate in response to cognate antigens during tumorigenesis. Therefore, we developed a genetic cancer mouse model in which we can track TST and SST differentiation longitudinally as liver cancers develop. We found that both TST and SST lost effector function over time, but while TST persisted long term and had a dysfunctional/exhausted phenotype (including expression of PD1, CD39, and TOX), SST exited cell cycle prematurely and disappeared from liver lesions. However, SST persisted in spleens in a dysfunctional TCF1+PD1- state: unable to produce effector cytokines or proliferate in response to ICB targeting PD1 or PDL1. Thus, our studies identify a dysfunctional T-cell state occupied by T cells reactive to SSA: a TCF1+PD1- state lacking in effector function, demonstrating that the type/specificity of tumor antigen may determine tumor-reactive T-cell differentiation.