CD8⁺ T Cells in the Lymph Node Play a Key Role in Immunotherapy Response

Recent studies have demonstrated that CD8⁺ T cells in secondary lymphoid organs, like tumor-draining lymph nodes (LN), are critical in mediating response to immune checkpoint blockade (ICB) therapy. However, evaluation of the relationship between the immune responses in the LN and the tumor in human patients remains incomplete. To examine this relationship, Rahim, Okholm, Jones, and colleagues used single-cell analyses of CD8⁺ T cells across tissues from patients with head and neck squamous cell carcinomas treated with perioperative anti–PD-L1. Results showed that progenitor-exhausted CD8⁺ T (Tpex) cells are abundant in uninvolved LNs, with these Tpex cells being clonally related to terminally exhausted CD8⁺ T (Tex) cells in the tumor microenvironment (TME), suggesting that CD8⁺ T-cell clones in different functional states exist in the LN and TME in patients and that the LN maintains a reservoir of functional antitumor CD8⁺ T cells. Tpex cells localized to the T zone in the uninvolved regional LNs (uiLN), which was reduced upon treatment with anti–PD-L1 prior to surgery, while intermediate Tex (Tex-int) cells were increased after treatment. Tex-int and Tpex cells were also more likely to be localized near each other after ICB therapy, suggesting that ICB treatment induces Tpex cells to transition to Tex-int cells. Moreover, both cell populations had elevated PD-1 expression and were localized in greater proximity to dendritic cells (DC), supporting a role for DCs in the uiLN in mediating antitumor CD8⁺ T-cell responses. Additionally, increased Tex-int cells expressing Ki-67 were detected in the blood after ICB treatment, which corresponded with LN responses. Metastases to the LN (metLN) impaired these response phenotypes, as more immunosuppressive niches surround Tpex and Tex-int cells as compared to uiLNs, and patients with metLNs also had blunted ICB responses in the blood. In summary, this work shows the crucial role of CD8⁺ T-cell responses in human LNs and suggests the development of immunotherapies that harness this antitumor immunity to improve outcomes.

Rahim MK, Okholm TLH, Jones KB, McCarthy EE, Liu CC, Yee JL, et al. Dynamic CD8⁺ T cell responses to cancer immunotherapy in human regional lymph nodes are disrupted in metastatic lymph nodes. Cell 2023;186:1127–43.

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