Early-like differentiation status of systemic PD-1CD8 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 (CD28CD27CD45RO, T) to PD-1 effector CD8 T cells (CD28CD27CD45RO, T) delineated responders to PD-1 blockade from progressors and was associated with prolonged progression-free survival (PFS) and durable clinical benefit. Moreover, PD-1CD8 T cells exhibited early responses after anti-PD-1 therapy and was the major fraction of cycling PD-1Ki67CD8 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.