biostudies-literatureMorgan DMNCI NIH HHSeadi3487https://www.ebi.ac.uk/biostudies/studies/S-EPMC11580689biostudies-literatureUnknown9(99)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 KScience immunologyExpansion of tumor-reactive CD8<sup>+</sup> T cell clonotypes occurs in the spleen in response to immune checkpoint blockade.PMC11580689P30 CA014051R37 CA273819Zagorulya MLove JCSpranger SDinter THorton BLBhandarkar VVan RMorgan DMfalseExpansion of tumor-reactive CD8<sup>+</sup> T cell clonotypes occurs in the spleen in response to immune checkpoint blockade.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 K2024-01-01T00:00:00Z2024 Sep2025-04-04T01:21:27.364Z2025-04-04T01:21:27.364ZS-EPMC115806893927000610.1126/sciimmunol.adi3487