Th7R Cells: CD4⁺ T-Cell Partners That Drive Tpex-Mediated Antitumor Immunity in the Tumor Microenvironment

The priming, expansion, and function of CD8⁺ T cells depend on CD4⁺ T-cell help via dendritic cells. Precursor exhausted T cells (Tpex) maintain self-renewal and supply cytotoxic CD8⁺ T cells in the tumor microenvironment (TME), but their CD4⁺ T-cell partners were unclear. We performed scRNA-seq, scTCR-seq, and mass cytometry on peripheral blood, tumor, and lymph nodes from lung cancer patients and identified that IL-7R ^high CCR6⁺ Th1-like CD4⁺ T cells (Th7R) are numerically and spatially partnered with Tpex. Th7R expressed lymphotoxin-β and CXCL13, correlated with high endothelial venules, and co-localized with Tpex in tertiary lymphoid structures. Th7R abundance correlated with Tpex numbers in TME and lymph nodes, and adoptive transfer of Th7R increased Tpex in a mouse model. In patients, Th7R and Tpex in TME were associated with better response to neoadjuvant PD-1 blockade therapy. These results suggest that Th7R act as partners of Tpex to support sustained antitumor T-cell immunity.