Myeloperoxidase promotes a tumorigenic microenvironment in non-small cell lung cancer

Abstract

Myeloperoxidase (MPO) is a heme peroxidase that is mainly expressed and secreted by neutrophils. The role of MPO in inflammatory diseases has been highlighted in recent years, but its role in tumor development remains unclear. Therefore, we investigated the role of MPO in non-small cell lung cancer (NSCLC). In silico analysis revealed a survival benefit in patients with NSCLC and low MPO expression. Furthermore, a syngeneic tumor model using MPO knockout (KO) mice revealed that mice lacking MPO had lower tumor growth than controls. The reduction in tumor size was accompanied by an increase in lymphoid populations, including natural killer cells and CD8+ T cells, suggesting a shift to a more anti-tumorigenic immune environment in MPO-KO mouse tumors. The T cell induced interferon-gamma (IFN-γ) expression was increased in MPO- KO tumors, indicating increased tumoricidal activity. CD8 depletion abolished the previously observed reduction in tumor size in MPO-KO mice, indicating that CD8+ T cells play an important role. In vitro, T cells treated with MPO showed reduced proliferation and IFN-γ expression. Furthermore, MPO could be internalized into T cells. Heparin pretreatment of T cells blocked MPO binding and internalization into T cells and reversed MPO-induced proliferation reduction. Interestingly, MPO+ lymphocytes were found in tumor samples from patients with NSCLC. Our findings suggest that MPO plays an immunosuppressive role in NSCLC.

Myeloperoxidase Alters Lung Cancer Cell Function to Benefit Their Survival

“…Previous studies in our laboratory have shown that MPO-deficient mice (MPO KO; C57BL/6 MPO −/− ) have up to a 40% reduction in tumour size compared to MPO wild-type mice (C57BL/6 MPO +/+ ) [ 29 ]. To further understand the role of MPO in the setting of lung cancer, we aimed to investigate whether MPO can alter the function of tumour cells in vitro.…”

“…Low MPO expression has been linked to a reduced risk of developing lung cancer [ 28 ]. Moreover, different studies have indicated a pro-tumorigenic function of MPO in the lung TME [ 29 , 40 ]. Recent studies from our laboratory showed that tumour-bearing MPO knock-out mice (MPO KO) had reduced tumour growth when compared to their wild-type (WT) littermates [ 29 ].…”

“…Moreover, different studies have indicated a pro-tumorigenic function of MPO in the lung TME [ 29 , 40 ]. Recent studies from our laboratory showed that tumour-bearing MPO knock-out mice (MPO KO) had reduced tumour growth when compared to their wild-type (WT) littermates [ 29 ]. Interestingly, MPO directly influenced CD8 + T-cell function in vitro and in vivo, thereby affecting tumour development [ 29 ].…”

“…Recent studies from our laboratory showed that tumour-bearing MPO knock-out mice (MPO KO) had reduced tumour growth when compared to their wild-type (WT) littermates [ 29 ]. Interestingly, MPO directly influenced CD8 + T-cell function in vitro and in vivo, thereby affecting tumour development [ 29 ]. Accordingly, we aimed to determine whether MPO can also influence cancer cell function and its mechanism of action.…”

“…All treatments were performed in DMEM without FBS or PS. For in vivo experiments, the murine KP cell line was generously provided by Dr. McGarry Houghton (FredHutch, Seattle, WA, USA) [ 29 ]. KP cells were maintained in DMEM with 10% FBS and 1% P/S at 37 °C, 5% CO 2 in a humidified atmosphere.…”