PD-1 antibody–bound progenitor-exhausted CD8+ T cells in lymph nodes boost PD-1–blockade anti-tumor immunity in gastrointestinal cancer

While progenitor-exhausted T cells (Tpex) expressing TCF1 and PD-1 are crucial for the therapeutic effect of immune checkpoint inhibitors (ICIs; therapeutic anti–PD-1 antibodies), the dynamics of ICI-bound Tpex are not fully understood. In this study, we investigated ICI-bound T cells in detail using combined sequencing analysis at the single cell level. By analyzing samples from gastrointestinal cancer patients with or without ICI treatment, we found that Tpex were enriched in proximal lymph nodes (LNs) and proliferated at a high rate after ICI treatment. Importantly, ICI high–bound Tpex in LNs shared T-cell receptor clonotypes with intratumoral exhausted CD8+ T cells (Tex), suggesting their migration to tumor sites after ICI treatment. These findings indicate that ICIs initially target PD-1+CD8+ Tpex in LNs, prompting their proliferation. Subsequently, these cells migrate to tumors and differentiate into Tex, thereby exerting anti-tumor immunity.