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.

中文翻译：

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肿瘤反应性 CD8 + T 细胞克隆型的扩增发生在脾脏中，以响应免疫检查点阻断


免疫检查点阻断 （ICB） 可增强 T 细胞对癌症的反应，从而使一小部分患者能够长期生存。响应慢性抗原刺激的 CD8 + T 细胞分化高度复杂，目前尚不清楚哪些 T 细胞分化状态在哪些解剖部位对 ICB 的反应至关重要。我们在脾脏白髓中鉴定了一个中度耗竭的群体，该群体响应 ICB 而经历实质性扩张并产生肿瘤浸润克隆型。全身抗原的增加使该群体的分化转向更循环的耗竭 KLR 状态，而缺乏交叉呈递的肿瘤抗原减少了其在脾脏中的分化。人血样中耗竭的 KLR CD8 + T 细胞的类似群体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响应 ICB 的 T 细胞克隆型分化和扩增的关键作用。