Inhibition of IL-18-mediated myeloid derived suppressor cell accumulation enhances anti-PD1 efficacy against osteosarcoma cancer

Abstract

Myeloid derived suppressor cells (MDSC) are very important in tumor immune evasion and they dramatically increased in peripheral blood of patients with osteosarcoma cancer. The association between MDSC and various cytokines has been studied in the peripheral blood. However, little is known about the mechanism drawing MDSC into tumor parenchyma. This study was to analyze the correlation between MDSC subsets and interleukin 18 (IL-18) level in osteosarcoma tumor model and its effect on the immunotherapy. MDSC were isolated from the blood and parenchyma and analyzed in the osteosarcoma tumor model. IL-18 levels were detected by enzyme-linked immunosorbent assay (ELISA) assay, real-time PCR, western blot and flow cytometry. Moreover, combination treatment with IL-18 inhibition and anti-PD1 was conducted to assess the therapeutic effects of IL-18 blockade. Results showed MDSC levels had a positive correlation with IL-18, suggesting IL-18 may attract MDSC into the parenchyma. IL-18 gene and protein expression significantly increased in blood and tumor lysates of tumor-bearing mice. Anti-IL-18 treatment significantly decreased G-MDSC and M-MDSC in the peripheral blood and tumor. Furthermore, combination therapy decreased the tumor burden and increased CD4+ and CD8+ T cell infiltration, as well as the production of interferon gamma (IFNγ) and granzyme B. Our study revealed a possible correlation between MDSC subsets and IL-18 inducing MDSC migration into the tumor tissue, in addition to provide the potential target to enhance the efficacy of immunotherapy in patients with osteosarcoma.

Reduced Expression of IL-1β and IL-18 Proinflammatory Interleukins Increases the Risk of Developing Cervical Cancer

“…Other studies have found that IL-18 exerts a control to maintain homeostasis between inflammation and repair of the lamina propria that lies beneath the epithelium (Dupaul-Chicoine et al, 2010). It is worth pointing out that, in osteosarcoma, increased IL-18 expression can be attributed to an increase in tumor resistance derived from the infiltration of suppressor cells of myeloid origin (Guan et al, 2017). However, in melanoma it has been observed that IL-18 enhances the antitumor response by inducing tumor-infiltrating CD8+ T lymphocytes (Kunert et al, 2017).…”

Herbal Medicines Attenuate PD-L1 Expression to Induce Anti-Proliferation in Obesity-Related Cancers

“…Alternatively, PD-1 mainly regulates effector T-cell activity within tissues and tumors, where the immune response is ongoing [12]. PD-L1 is involved in evading immune surveillance [13] The B-and T-lymphocyte attenuator (BTLA) is a checkpoint co-inhibitory receptor categorized into the CD28 superfamily (immunoglobulin (Ig) superfamily) [14]. It is present in a large range of immune cells, including T-cells, B cells, and natural killer (NK) cells.…”

The Sweet Surrender: How Myeloid Cell Metabolic Plasticity Shapes the Tumor Microenvironment

“…In a preclinical renal cell carcinoma mouse model, Rayman and colleagues observed that depleting MDSCs with TKI, sunitinib together with checkpoint blockade by anti-PD1 antibody co-treatment resulted in significantly more CD8+ T cells in the tumor (Rayman et al, 2015). This is accompanied by an increased production of pro-inflammatory IFNγ and granzyme B (Guan et al, 2017). More importantly, a high percentage of tumor-infiltrating CD8+ T cells expressed CD107a, which is involved in the cytotoxic killing of tumor target cells (Rayman et al, 2015).…”

“…More importantly, a high percentage of tumor-infiltrating CD8+ T cells expressed CD107a, which is involved in the cytotoxic killing of tumor target cells (Rayman et al, 2015). Other approaches such as monoclonal antibody therapy against CXCR2 (Highfill et al, 2014), CCL2 (Wang et al, 2018), or IL-18 (Guan et al, 2017) to inhibit MDSCs trafficking into tumors also successfully induces tumor regression upon anti-PD1 treatment. These studies suggest that resistance to immune-checkpoint blockade might be alleviated by therapeutic strategies that reprogram dominant myeloid responses.…”