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 clonotype based on single-cell RNA-sequencing data. Unsupervised clustering analysis uncovered the presence of a new CD4(+) T-cell metacluster in the CD62L(low) 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 IL7 receptor and TCF7. The frequency of these cells in the peripheral blood significantly correlated with progression-free survival and overall survival of patients with lung cancer 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 CD62L(low) 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. SIGNIFICANCE: The identification of a new CD4(+) T-cell metacluster that corresponds with immune status could guide effective tumor treatment by predicting response to immunotherapy using peripheral blood samples from patients.