免疫检查点阻断 (ICB) 增强 T 细胞对癌症的反应，使一小部分患者能够长期生存。 CD8 T 细胞响应慢性抗原刺激的分化非常复杂，目前尚不清楚哪些 T 细胞分化状态在哪些解剖部位对于 ICB 的反应至关重要。我们在脾脏白髓中发现了一个中度耗尽的群体，该群体在 ICB 的作用下经历了大幅扩张，并产生了肿瘤浸润克隆型。全身抗原的增加使该群体的分化转向更循环衰竭的 KLR 状态，而交叉呈递的肿瘤抗原的缺乏减少了其在脾脏中的分化。人类血液样本中类似的耗尽的 KLR CD8 T 细胞群表现出肿瘤运输能力减弱。总的来说，我们的数据证明了脾脏内抗原密度对于响应 ICB 的 T 细胞克隆型的分化和扩增的关键作用。

Immune checkpoint blockade (ICB) enhances T cell responses against cancer, leading to long-term survival in a fraction of patients. CD8+ T cell differentiation in response to chronic antigen stimulation is highly complex, and it remains unclear precisely which T cell differentiation states at which anatomic sites are critical for the response to ICB. We identified an intermediate-exhausted population in the white pulp of the spleen that underwent substantial expansion in response to ICB and gave rise to tumor-infiltrating clonotypes. Increased systemic antigen redirected differentiation of this population toward a more circulatory exhausted KLR state, whereas a lack of cross-presented tumor antigen reduced its differentiation in the spleen. An analogous population of exhausted KLR CD8+ T cells in human blood samples exhibited diminished tumor-trafficking ability. Collectively, our data demonstrate the critical role of antigen density within the spleen for the differentiation and expansion of T cell clonotypes in response to ICB.