Plasma Gelsolin Confers Chemoresistance in Ovarian Cancer by Resetting the Relative Abundance and Function of Macrophage Subtypes

Abstract

Ovarian cancer (OVCA) is the most lethal gynaecological cancer with a 5-year survival rate less than 50%. Despite new therapeutic strategies, such as immune checkpoint blockers (ICBs), tumor recurrence and drug resistance remain key obstacles in achieving long-term therapeutic success. Therefore, there is an urgent need to understand the cellular mechanisms of immune dysregulation in chemoresistant OVCA in order to harness the host’s immune system to improve survival. The over-expression of plasma gelsolin (pGSN) mRNA is associated with a poorer prognosis in OVCA patients; however, its immuno-modulatory role has not been elucidated. In this study, for the first time, we report pGSN as an inhibitor of M1 macrophage anti-tumor functions in OVCA chemoresistance. Increased epithelial pGSN expression was associated with the loss of chemoresponsiveness and poor survival. While patients with increased M1 macrophage infiltration exhibited better survival due to nitric-oxide-induced ROS accumulation in OVCA cells, cohorts with poor survival had a higher infiltration of M2 macrophages. Interestingly, increased epithelial pGSN expression was significantly associated with the reduced survival benefits of infiltrated M1 macrophages, through apoptosis via increased caspase-3 activation and reduced production of iNOS and TNFα. Additionally, epithelial pGSN expression was an independent prognostic marker in predicting progression-free survival. These findings support our hypothesis that pGSN is a modulator of inflammation and confers chemoresistance in OVCA, in part by resetting the relative abundance and function of macrophage subtypes in the ovarian tumor microenvironment. Our findings raise the possibility that pGSN may be a potential therapeutic target for immune-mediated chemoresistance in OVCA.

Identification of the immune subtype of ovarian cancer patients by integrated analyses of transcriptome and single-cell sequencing data

“…In addition, immunotherapeutic drugs combined with other classical drugs have also shown good efficacy in a variety of tumors, such as ICIs combined with angiogenesis inhibitors for liver cancer or combined with BRAF inhibitors for advanced melanoma with BRAF V600 mutation 14 , 15 . Moreover, the proportion of M1/M2 macrophages has also been preliminarily studied in the prognosis evaluation of ovarian cancer 16 , 17 . At present, there are also some studies related to immunotherapy for OC, such as programmed cell death-ligand 1 (PD-L1) or programmed cell death-1 (PD-1) combined chemotherapy or angiogenesis inhibitors for recurrent OC, which are in different stages of clinical trials 18 – 21 .…”

Emerging roles of plasma gelsolin in tumorigenesis and modulating the tumor microenvironment

“…It has been reported that pGSN selectively suppresses the viability of antitumor M1 macrophages but not pro‐tumor M2 macrophages in ovarian cancer 53 . This study also revealed that chemoresistant ovarian cancer cells can release more extracellular vesicles enriched in pGSN to induce apoptosis in M1 macrophages and reduce the secretion of inducible nitric oxide synthase (iNOS) and TNFα 53 .…”

“…53 This study also revealed that chemoresistant ovarian cancer cells can release more extracellular vesicles enriched in pGSN to induce apoptosis in M1 macrophages and reduce the secretion of inducible nitric oxide synthase (iNOS) and TNFα. 53 Particularly, high pGSN-low M1/M2 profile in tumor of ovarian cancer patients shows the poorest progression-free survival, suggesting that pGSN could be an independent prognostic biomarker and a therapeutic target for immune-mediated chemoresistance in ovarian cancer. 53 In addition, the pGSN-rich extracellular vesicles released by chemoresistant ovarian cancer cells can also induce apoptotic cell death of CD8 T cells via FLIP downregulation and caspase-3 activation, resulting in decreased levels of IFNγ.…”

“…53 Particularly, high pGSN-low M1/M2 profile in tumor of ovarian cancer patients shows the poorest progression-free survival, suggesting that pGSN could be an independent prognostic biomarker and a therapeutic target for immune-mediated chemoresistance in ovarian cancer. 53 In addition, the pGSN-rich extracellular vesicles released by chemoresistant ovarian cancer cells can also induce apoptotic cell death of CD8 T cells via FLIP downregulation and caspase-3 activation, resulting in decreased levels of IFNγ. 54 Of note, the treatment of pGSN-rich extracellular vesicles did not affect the proliferation of CD4 T cells but further promote their polarization toward type 2 helper cells.…”

“…It has been reported that pGSN selectively suppresses the viability of antitumor M1 macrophages but not pro‐tumor M2 macrophages in ovarian cancer 53 . This study also revealed that chemoresistant ovarian cancer cells can release more extracellular vesicles enriched in pGSN to induce apoptosis in M1 macrophages and reduce the secretion of inducible nitric oxide synthase (iNOS) and TNFα 53 . Particularly, high pGSN‐low M1/M2 profile in tumor of ovarian cancer patients shows the poorest progression‐free survival, suggesting that pGSN could be an independent prognostic biomarker and a therapeutic target for immune‐mediated chemoresistance in ovarian cancer 53 .…”