CD4⁺ T-cell Immunity in the Peripheral Blood Correlates with Response to Anti-PD-1 Therapy

Accumulating evidence indicates that CD8⁺ T cells in the tumor microenvironment and systemic CD4⁺ T-cell immunity play an important role in mediating durable antitumor responses. We longitudinally examined T-cell immunity in the peripheral blood of patients with non-small lung cancer and found that responders had significantly (P < 0.0001) higher percentages of effector, CD62L^low CD4⁺ T cells prior to PD-1 blockade. Conversely, the percentage of CD25⁺FOXP3⁺ CD4⁺ T cells was significantly (P = 0.034) higher in nonresponders. We developed a formula, which demonstrated 85.7% sensitivity and 100% specificity, based on the percentages of CD62L^low CD4⁺ T cells and CD25⁺FOXP3⁺ cells to predict nonresponders. Mass cytometry analysis revealed that the CD62L^low CD4⁺ T-cell subset expressed T-bet⁺, CD27^-, FOXP3^-, and CXCR3⁺, indicative of a Th1 subpopulation. CD62L^low CD4⁺ T cells significantly correlated with effector CD8⁺ T cells (P = 0.0091) and with PD-1 expression on effector CD8⁺ T cells (P = 0.0015). Gene expression analysis revealed that CCL19, CLEC-2A, IFNA, IL7, TGFBR3, CXCR3, and HDAC9 were preferentially expressed in CD62L^low CD4⁺ T cells derived from responders. Notably, long-term responders, who had >500-day progression-free survival, showed significantly higher numbers of CD62L^low CD4⁺ T cells prior to PD-1 blockade therapy. Decreased CD62L^low CD4⁺ T-cell percentages after therapy resulted in acquired resistance, with long-term survivors maintaining high CD62L^low CD4⁺ T-cell percentages. These results pave the way for new treatment strategies for patients by monitoring CD4⁺ T-cell immune statuses in their peripheral blood.