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Targeting Myeloid-Derived Suppressor Cells Derived From Surgical Stress: The Key to Prevent Post-surgical Metastasis.

ABSTRACT: Myeloid-derived suppressor cells (MDSCs) are known to play an essential part in tumor progression under chronic stress settings through their manipulation of adaptive and innate immune systems. Previous researches mainly focus on MDSC's role in the chronic tumor immune environment. In addition, surgery can also serve as a form of acute stress within the patient's internal environment. Nevertheless, the part that MDSCs play in post-surgical tumor development has not gained enough attention yet. Although surgery is known to be an effective definite treatment for most localized solid tumors, there are still plenty of cancer patients who experience recurrence or metastasis after radical resection of the primary tumor. It is believed that surgery has the paradoxical capability to enhance tumor growth. Many possible mechanisms exist for explaining post-surgical metastasis. We hypothesize that surgical resection of the primary tumor can also facilitate the expansion of MDSCs and their pro-tumor role since these surgery-induced MDSCs can prepare the pre-metastatic niche (the "soil") and at the same time interact with circulating tumor cells (the "seeds"). This vicious, reciprocal mechanism is a crucial point in the emergence of post-surgical metastasis. According to our hypothesis, MDSCs can be the precise target to prevent cancer patients from post-surgical recurrence and metastasis during the perioperative phase to break the wretched cycle and provide better long-term survival for these patients. Future studies are needed to validate this hypothesis.

SUBMITTER: Zhu S

PROVIDER: S-EPMC8695559 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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-Rag1tm1Mom/J, and B6.129P2(SJL)-Myd88tm1.1Defr/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-Rag1tm1Mom/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-Rag1tm1Mom/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)-Myd88tm1.1Defr/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.

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Targeting Myeloid-Derived Suppressor Cells Derived From Surgical Stress: The Key to Prevent Post-surgical Metastasis.

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