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

Jae Heun Chung; Jong Seong Ha; Jaewoo Choi; Sang Mo Kwon; Mi Sook Yun; Taehwa Kim; Doosoo Jeon; Seong Hoon Yoon; Yun Seong Kim

doi:10.21037/tcr-21-2506

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

Transl Cancer Res. 2022 Feb;11(2):316-326. doi: 10.21037/tcr-21-2506.

Authors

Jae Heun Chung^#^{1

2}, Jong Seong Ha^#^{3

4}, Jaewoo Choi³, Sang Mo Kwon^{3

4}, Mi Sook Yun², Taehwa Kim^{1

2}, Doosoo Jeon^{1

2}, Seong Hoon Yoon^{1

2}, Yun Seong Kim^{1

2}

Affiliations

¹ Department of Internal Medicine, College of Medicine, Pusan National University, Pusan National University Yangsan Hospital, Yangsan, South Korea.
² Research Institute of Convergence Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, South Korea.
³ Laboratory of Regenerative Medicine and Stem Cell Biology, Department of Physiology, Medical Research Institute, School of Medicine, Pusan National University, Yangsan, South Korea.
⁴ BK21 GRAND Convergence Medical Science Eduation Rsearch Center, Pusan National University, Yangsan, South Korea.

^# Contributed equally.

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.

Keywords: CD8 T cells; Granzyme B; immunotherapy; non-small cell lung cancer (NSCLC); programmed death-1.