Myeloid Derived Suppressor Cells: Key Drivers of Immunosuppression in Ovarian Cancer

Abstract

The presence of tumor infiltrating lymphocytes (TILs) is associated with a longer overall survival in advanced stage epithelial ovarian cancer. Despite the prognostic impact of TILs, response to checkpoint-inhibitors and antigen-specific active immunotherapy is limited in ovarian cancer. The goal of our study was to investigate the interaction between ovarian cancer and the innate and adaptive immune system in the ID8-fLuc syngeneic ovarian cancer mouse model. For the in vivo experiments C57BL/6, B6.129S7-Rag1 tm1Mom /J, and B6.129P2(SJL)-Myd88 tm1.1Defr /J mice were inoculated with ID8-fLuc. In vivo depletion experiments were performed using clodronate liposomes (CL), anti-CD8a, anti-GR1, anti-colony stimulating factor 1 (anti-CSF1), and TMβ1 (anti-CD122). Immune read out was performed by fluorescent activated cell sorting analysis for effector T cells, regulatory T cells, natural killer cells, B cells, macrophages, and myeloid derived suppressor cells (MDSC), immunohistochemistry for MDSC and tumor-associated macrophages (TAM) and immunofluorescence for M1 and M2 TAM in the vascular context. The effect of MDSC on T cell proliferation and phenotype were studied in vitro . We discovered that the absence of T and B cells did not influence tumor growth or survival of B6.129S7-Rag1 tm1Mom /J mice compared to immunocompetent C57BL/6 mice. CL-induced macrophage depletion promoted tumor proliferation and shortened survival in C57BL/6 mice ( p = 0.004) and in B6.129S7-Rag1 tm1Mom /J mice ( p = 0.0005). During CL treatment, we observed a clear increase of pro-inflammatory cytokines ( p ≤ 0.02) and monocytic MDSC ( p ≤ 0.01). Selective depletion of MDSC by anti-GR1 improved survival, certainly in comparison to mice treated with anti-CSF1 ( p = 0.01—median survival 91 vs. 67.5 days). B6.129P2(SJL)-Myd88 tm1.1Defr /J mice displayed to a longer median survival compared to C57BL/6 mice (90 vs. 76 days). MDSC activated by ID8-fLuc conditioned medium or ascites of tumor-bearing mice showed T cell suppressive functions in vitro . Based on these findings, we conclude that the adaptive immune system does not efficiently control tumor growth in the ID8-fLuc model. In addition, we discovered a prominent role for MDSC as the driver of immunosuppression in the ID8-fLuc ovarian cancer mouse model.

Myeloid-derived suppressor cells at diagnosis may discriminate between benign and malignant ovarian tumors

“…From a clinical point of view, this comparison is most relevant. In contrast to the focus on the adaptive immune system in ovarian cancer since 2003, this study clearly indicates a role for the innate immune system, as was also demonstrated by our group in an ovarian cancer mouse model 18. In subgroup analyses, a substantial role for the adaptive immune system seems to be maintained.…”

Immune Checkpoint Blockade in Gynecologic Cancers: State of Affairs

“…Overall, even though there is good outcome in some monotherapy trials blocking PD-1 or PD-L1 in EC (up to 57.1% ORR), a greater cohort of EC patients may benefit in combination therapy designs using ICI and other agents, which may potentially alleviate suppressor mechanisms in the tumor microenvironment (TME). Combination therapy has the potential to afford additive or synergistic benefits, as compared to single agent treatment, as well as to overcome resistance mechanisms that are observed with ICI monotherapy administration, due to the upregulation of alternative immune checkpoint molecules or to emerging resistance caused by the presence of cells such as myeloid-derived suppressor cells (MDSCs) [61][62][63][64][65]. Currently, several clinical trials are ongoing with ICI treatment in EC patients, which are used in combination with cytotoxic chemotherapy, other ICI, vaccines and other immunotherapies, or targeted therapies [25,26,29,32,66].…”

“…Additionally, myeloid-derived suppressor cells (MDSCs) enhance stemness and promote metastasis, induce resistance to therapy, and limit the anti-tumor functions of T cells through MDSC signature molecules, nitric oxide (NO), and arginase-1 (Arg-1) [91,92]. Elevated MDSC numbers are highly associated with resistance to conventional and novel therapies [61,62,93].…”

Opposite Macrophage Polarization in Different Subsets of Ovarian Cancer: Observation from a Pilot Study

“…However, most data in this regard exist on the adaptive immune system [8,9]. Nevertheless, our group recently provided evidence on the importance of the innate immune system in ovarian cancer [10,11]. The major players within this innate immune system are dendritic cells, myeloid derived suppressor cells, and macrophages.…”