ANKRD22 is a potential novel target for reversing the immunosuppressive effects of PMN-MDSCs in ovarian cancer.

BACKGROUND

Ovarian cancer is the deadliest type of malignant gynecological tumor. Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are involved ovarian cancer and are closely related to adverse outcomes. However, the immunosuppressive mechanism of PMN-MDSCs remains elusive.

METHODS

The types and numbers of ANKRD22-expressing cells were investigated by bioinformatics analysis and immunohistochemical staining. C57BL/6 mice were constructed with CRISPR-Cas9 technology. Mouse PMN-MDSCs were obtained from bone marrow (BM)-derived CD11bLy6GLy6C cells sorted by fluorescence-activated cell sorting with treatment of GM-CSF and IL-6, and the immunosuppressive activity of PMN-MDSCs was evaluated by flow cytometry (FCM) and ELISA. The expression level of CCR2 and the exogenous glucose uptake capacity were determined by FCM. RT-qPCR was used to detect expression in CD11bHLA-DRCD14CD15 cells from human ovarian cancer tissues, and the correlations of expression with the clinical characteristics and prognosis of patients were evaluated by the χ test.

RESULTS

We identified a novel protein involved in regulating the immunosuppressive ability of PMN-MDSCs, ANKRD22. expression was high in mouse CD11bLy6GLy6C cells and could be significantly downregulated after exposure to a simulated microenvironmental stimulus. Knockout of increased the expression level of CCR2 of CD11bLy6GLy6C cells and the immunosuppressive activity of PMN-MDSCs. BM-derived CD11bLy6GLy6C cells of mice significantly promoted the proliferation of ovarian cancer cells in tumor xenograft mouse models. Mechanistically, RNA sequencing showed that expression was obviously increased in -knockout BM-derived CD11bLy6G Ly6C cells and that ectopic expression of increased the levels of , , and in PMN-MDSCs derived from BM-derived CD11bLy6GLy6C cells. Surprisingly, an ANKRD22-activating candidate small-molecule compound attenuated the immunosuppressive activity of PMN-MDSCs. Finally, we found that low levels in CD11bHLA-DRCD14CD15 cells derived from primary ovarian tissues were associated with a more advanced International Federation of Gynecology and Obstetrics stage, a higher recurrence rate, and a higher neutrophil-to-lymphocyte ratio.

CONCLUSIONS

These results suggest that ANKRD22 is a potential novel target for reversing the immunosuppressive effects of PMN-MDSCs.