| Summary: | Abstract 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+, TEEM) to PD‐1+ effector CD8+ T cells (CD28−CD27−CD45RO−, TE) 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 TEEM 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.
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