Single-cell analysis reveals a CD4+ T cell cluster that correlates with PD-1 blockade efficacy.

CD4+ T-cell immunity helps clonal proliferation, migration, and cancer cell killing activity of CD8+ T cells and is essential in antitumor immune responses. To identify CD4+ T cell clusters responsible for antitumor immunity, we simultaneously analyzed the naïve-effector state, Th polarization, and T cell receptor (TCR) clonotype based on single-cell RNA sequencing data. Unsupervised clustering analysis uncovered the presence of a new CD4+ T cell metacluster in the CD62Llow CD4+ T cell subpopulation, which contained multicellular clonotypes associated with efficacy of programmed death-ligand 1 (PD-1) blockade therapy. The CD4+ T-cell metacluster consisted of CXCR3+CCR4-CCR6+ and CXCR3-CCR4-CCR6+ cells and was characterized by high expression of IL-7 receptor and TCF7. The frequency of these cells in the peripheral blood significantly correlated with progression-free survival (PFS) and overall survival (OS) of lung cancer patients after PD-1 blockade therapy. In addition, the CD4+ metacluster in the peripheral blood correlated with CD4+ T-cell infiltration in the tumor microenvironment, whereas peripheral Th1 correlated with local CD8+ T-cell infiltration. Together, these findings suggest that CD62Llow CCR4-CCR6+ CD4+ T cells form a novel metacluster with predictive potential of the immune status and sensitivity to PD-1 blockade, which may pave the way for personalized antitumor immunotherapy strategies for patients.