Early‐like differentiation status of systemic PD‐1(+) CD8 (+) T cells predicts PD‐1 blockade outcome in non‐small cell lung cancer

OBJECTIVES: Despite remarkable advances in the treatment of non‐small cell lung cancer (NSCLC) with anti‐programmed death (PD)‐1 therapy; only a fraction of patients derives durable clinical benefit. In this study, we investigated whether the differentiation status of systemic CD8(+) T cells predicts the outcome of PD‐1 blockade in NSCLC. METHODS: We carried out a prospective study on a total of 77 NSCLC patients receiving anti‐PD‐1 blockers, among which 47 patients were assigned as a discovery cohort and 30 patients as a validation cohort. Peripheral blood samples were obtained at baseline and upon multiple therapy cycles and analyzed by multi‐parameter flow cytometry. RESULTS: We found that a higher baseline ratio of PD‐1(+) early effector memory CD8(+) T cells (CD28(+)CD27(−)CD45RO(+), T(EEM)) to PD‐1(+) effector CD8(+) T cells (CD28(−)CD27(−)CD45RO(−), T(E)) delineated responders to PD‐1 blockade from progressors and was associated with prolonged progression‐free survival (PFS) and durable clinical benefit. Moreover, PD‐1(+)CD8 T(EEM) cells exhibited early responses after anti‐PD‐1 therapy and was the major fraction of cycling PD‐1(+)Ki67(+)CD8(+) T cells to expand specifically with positive impact on PFS. CONCLUSION: These findings provide insights into how the baseline differentiation status of the peripheral immune system determines responses to PD‐1‐targeted therapies.