Granzyme B for predicting the durable clinical benefit of anti-PD-1/PD-L1 immunotherapy in patients with non-small cell lung cancer

BACKGROUND: To identify immunotherapy biomarkers, we examined granzyme B levels in peripheral blood PD-1(+) CD8(+) T cells and their relationship with treatment outcomes in patients with non-small cell lung cancer (NSCLC). METHODS: To evaluate the association of granzyme B with response to immunotherapy, we tested blood samples obtained from 16 patients with stage IIIC to IV NSCLC receiving immune-checkpoint inhibitor treatment. We used flow cytometry to measure the change in the percentage of PD1(+) CD8(+) T cells expressing granzyme B before (t0) and after (t1) immunotherapy, and we evaluated for an association with tumor response to therapy, progression-free survival (PFS) and overall survival (OS). Additionally, we measured immune markers correlated with immunotherapy response by enzyme-linked immunosorbent assay. RESULTS: We found that the sequential change of granzyme B+ T cells after immunotherapy (t1/t0) significantly predicted durable clinical benefit (DCB) compared to no clinical benefit (NCB) (P=0.048), and prolonged PFS (P=0.025). Patients who demonstrated a PD-L1 tumor proportion score (TPS) >50% showed NCB if patients had low granzyme B t1/t0 levels (<0.805). Additionally, all patients with 1% PD-L1 TPS (or higher) and high granzyme B t1/t0 (≥0.805) showed DCB. Therefore, granzyme B t1/t0 may be an adjunctive marker with available PD-L1 TPS. CONCLUSIONS: Our findings revealed that sequential change in granzyme B might be utilized as a predictive biomarker of immune checkpoint inhibitor monotherapy.