CD244⁺ polymorphonuclear myeloid‑derived suppressor cells reflect the status of peritoneal dissemination in a colon cancer mouse model

Abstract

Despite the recent development of chemotherapeutic agents, the prognosis of colorectal cancer (CRC) patients with peritoneal dissemination (PD) remains poor. The tumor immune microenvironment (TIME) has drawn attention as a key contributing factor of tumor progression. Of TIME components, myeloid-derived suppressor cells (MDSCs) are considered to play a responsible role in the immunosuppressive characteristics of the TIME. MDSCs are classified into two major subsets: Monocytic MDSCs (M-MDSCs) and polymorphonuclear MDSCs (PMN-MDSCs). Therefore, we hypothesize that MDSCs would play important roles in the PD-relevant TIME and PD progression. To address this hypothesis, we established PD mouse models. As the PD nodules consisted scarcely of immune cells, we focused on the peritoneal cavity, but not PD nodule, to evaluate the PD-relevant TIME. As a result, intraperitoneal PMN-MDSCs were found to be substantially increased in association with PD progression. Based on these results, we phenotypically and functionally verified the usefulness of CD244 for identifying PMN-MDSCs. In addition, the concentrations of interleukin (IL)-6 and granulocyte-colony stimulating factor (G-CSF) were significantly increased in the peritoneal cavity, both of which were produced by the tumors and thought to contribute to the increases in the PMN-MDSCs. In vivo depletion of the PMN-MDSCs by anti-Ly6G monoclonal antibody (mAb) significantly inhibited the PD progression and reverted CD4 + and CD8 + T cells in the peritoneal cavity and the peripheral blood. Collectively, these results suggest that the targeted therapy for PMN-MDSCs would provide not only new therapeutic value but also a novel strategy to synergize with T-cell-based immunotherapy for CRC-derived PD.

Targeting AURKA in treatment of peritoneal tumor dissemination in gastrointestinal cancer

“…Recent studies have revealed the landscape of i.p. immunity mediated by not only inflammatory macrophages [9] , but also immunosuppressive cells, such as MDSCs [31] and Tregs [32] . IL33 and GDF15 might be, at least partly, underlying the identified mechanisms.…”

Vaccine Based on Dendritic Cells Electroporated with an Exogenous Ovalbumin Protein and Pulsed with Invariant Natural Killer T Cell Ligands Effectively Induces Antigen-Specific Antitumor Immunity

“…The procedures used in this experiment have been published previously [ 25 ]. Briefly, female C57BL/6J mice (8–12 weeks old) were purchased from CLEA Japan (Tokyo, Japan).…”

“…The procedures used in this experiment have been published previously [ 25 ]. Briefly, the EG7 cell line (a clone of EL4 murine thymoma cells expressing OVA) was purchased from American Type Culture Collection (Manassas, VA, USA).…”

“…The procedures used in this experiment have been published previously [ 25 , 26 ]. Immune cells were evaluated in each experiment and treated with FcR blocking reagent (Miltenyi Biotec, Bergisch Gladbach, Germany), stained with fluorescence-labeled antibodies as indicated, and incubated for 20 min at 4 °C in phosphate buffered saline (PBS) containing 0.1% bovine serum albumin.…”

“…The procedures used in this experiment have been published previously and applied with minor modifications [ 25 , 27 , 28 ]. Briefly, spleens were harvested from mice and mechanically minced to collect splenocytes.…”