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

Abstract

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.

Spatial proteomic profiling of tumor and stromal compartments in non‐small‐cell lung cancer identifies signatures associated with overall survival

“…It has been shown that high GZMB is associated with the increased cytotoxic activity of tumor‐infiltrating lymphocytes (TILs) and improved disease‐free survival (DFS) and OS in multiple cancer types. 62 , 63 However, GZMB expression alone or coupled with markers like PD‐L1 can variably affect both recurrence‐free survival (RFS) and OS. 62 , 64 , 65 Our study supports these contradictory data by demonstrating that high GZMB expression is linked with poor survival.…”

“…Multivariate analysis for the stroma confirms the unfavorable impact of LAG3, B7‐H3 and PDL1, implying that when other covariates are controlled, the adverse effects of these markers become more pronounced. It has been shown that high GZMB is associated with the increased cytotoxic activity of tumor‐infiltrating lymphocytes (TILs) and improved disease‐free survival (DFS) and OS in multiple cancer types 62,63 . However, GZMB expression alone or coupled with markers like PD‐L1 can variably affect both recurrence‐free survival (RFS) and OS 62,64,65 .…”

Granzyme B Expression in the Tumor Microenvironment as a Prognostic Biomarker for Patients with Triple-Negative Breast Cancer

“…GZMB is associated with liver cancer progression [ 6 ] and is a potential prognostic marker of colorectal cancer [ 7 ]. Furthermore, serial changes in GZMB expression in non-small-cell lung cancer may serve as a biomarker for monitoring monotherapy with immune checkpoint inhibitors [ 8 , 9 ]. In breast cancer immunotherapy, the role of GZMB in the tumor microenvironment is also important [ 10 ].…”

The feasibility of granzyme B levels using an amperometric immunosensor for lung cancer detection

“…The use of granzyme B nanoparticles and positron emission tomography imaging has enabled us to quantitatively detect responsiveness to immunotherapy in accordance with tumor volume reduction (13). Previously, we also reported that the measurement of granzyme B levels in blood samples from patients with lung cancer could predict immunotherapy outcomes (14). Interestingly, the number of granzyme B-secreting NK T-like, NK, and CD8 + T cells and their granzyme B contents are decreased in lung cancer tissues compared to those in non-lung cancer tissues (15,16).…”