Granzyme B is correlated with clinical outcome after PD-1 blockade in patients with stage IV non-small-cell lung cancer

Abstract

BackgroundA minority of patients with advanced non-small-cell lung cancer (NSCLC) benefit from treatment with immune checkpoint inhibitors (ICIs). Ineffective effector function of activated T and NK cells may lead to reduced tumor cell death, even when these activated effector cells are released from their immune checkpoint brake. Hence, in this study we aimed to assess the association of baseline serum granzyme B, as well as germline variation of theGZMBgene, with clinical outcome to programmed cell death protein 1 (PD-1) blockade.MethodsA total of 347 patients with stage IV NSCLC who started nivolumab treatment between June 2013 and June 2017 were prospectively included. Baseline serum and whole blood was available, allowing for protein quantification and targeted DNA sequencing. Clinical outcome was based on best overall response (BOR) according to Response Evaluation Criteria in Solid Tumors, V.1.1, progression-free survival (PFS), and overall survival (OS).ResultsPatients with low serum levels of granzyme B had worse PFS (HR: 1.96; 95% CI: 1.12 to 3.43; p=0.018) and worse OS (HR: 2.08; 95% CI: 1.12 to 3.87; p=0.021) than patients with high baseline serum levels. To validate the findings, germline variation ofGZMBrs8192917 was assessed. Patients with homozygous and heterozygous variants ofGZMBrs8192917 had worse BOR (OR: 1.60; 95% CI: 1.01 to 2.52; p=0.044) and worse PFS (HR: 1.38; 95% CI:1.02 to 1.87; p=0.036) than wild types.ConclusionsA low baseline serum level of granzyme B and germline variation ofGZMBwas associated with worse clinical outcome in NSCLC, emphasizing the relevance and additional value of monitoring germline genetic variations which mirror cytotoxic functions of T cells in ICI therapy.Trail registration numberDutch Trial Registry (NL6828).

Germline Variation in PDCD1 Is Associated with Overall Survival in Patients with Metastatic Melanoma Treated with Anti-PD-1 Monotherapy

“…As observed previously in patients with non-small cell lung cancer (NSCLC) [36], patients with heterozygous or homozygous variation of GZMB c.128C > A have significantly worse PFS and OS after anti-PD-1 monotherapy in univariable analysis. After correction for baseline characteristics, however, these associations did not retain significance.…”

Preclinical Evaluation of Recombinant Human IL15 Protein Fused with Albumin Binding Domain on Anti-PD-L1 Immunotherapy Efficiency and Anti-Tumor Immunity in Colon Cancer and Melanoma

“…Granzyme-B, the granule protease secreted by NK and CD8 + T cells, induces apoptosis through BAX/BAK-mediated mitochondrial apoptotic pathway [ 47 ]. The increased level of granzyme-B in serum or tumor was correlated with favorable outcomes in patients with colorectal cancer or NSCLC [ 48 , 49 ]. In our results indicated the combination group presented significantly higher expression of granzyme-B and apoptotic proteins (BAX and cleaved-caspase-3) in CT-26 or B16-F10 tumor tissues compared to hIL15-ABD or anti-PD-L1 therapy ( Figure 5 I–K and Figure 4 N–P).…”

Unsupervised Hierarchical Clustering Identifies Immune Gene Subtypes in Gastric Cancer

“…Many immunotherapeutic drugs including CTLA-4 and PD-1 inhibitors eliminate cancer cells by increasing IFN γ expression. Hurkmanns et al found that lower granzyme B levels in patients with metastatic cancer favored tumor growth by halting the antitumor immunity response by cytotoxic immune cells ( Hurkmans et al, 2020 ). Co-stimulatory molecules such as CD86 which are expressed on mature DCs are critical in the activation of naïve T cells ( Hubo et al, 2013 ).…”