Exosomal Plasma Gelsolin Is an Immunosuppressive Mediator in the Ovarian Tumor Microenvironment and a Determinant of Chemoresistance

Abstract

Ovarian Cancer (OVCA) is the most fatal gynecologic cancer and has a 5-year survival rate less than 45%. This is mainly due to late diagnosis and drug resistance. Overexpression of plasma gelsolin (pGSN) is key contributing factor to OVCA chemoresistance and immunosuppression. Gelsolin (GSN) is a multifunctional protein that regulates the activity of actin filaments by cleavage, capping, and nucleation. Generally, it plays an important role in cytoskeletal remodeling. GSN has three isoforms: cytosolic GSN, plasma GSN (pGSN), and gelsolin-3. Exosomes containing pGSN are released and contribute to the progression of OVCA. This review describes how pGSN overexpression inhibits chemotherapy-induced apoptosis and triggers positive feedback loops of pGSN expression. It also describes the mechanisms by which exosomal pGSN promotes apoptosis and dysfunction in tumor-killing immune cells. A discussion on the potential of pGSN as a prognostic, diagnostic, and therapeutic marker is also presented herein.

Keywords: T cells; apoptosis; chemoresistance; extracellular vesicles (EVs); immune cells; macrophages; ovarian cancer; plasma gelsolin (pGSN); tumor microenvironment (TME).

Figure 1

Gelsolin isoforms and structure. (A) The pGSN, cGSN, and gelsolin-3 are encoded by a single gene as a result of alternative splicing and different transcriptional initiation sites. These isoforms contain at least 14 exons. Each isoform is characterized by a 5′-end arrangement; A unique 5′ untranslated region of cGSN is formed by exons 1 and 2; The unique 5′-end of pGSN is formed by exon 3. These encode the signal peptide and the first 21 residues of pGSN; The unique 5′-end of Gelsolin-3 is arranged in the area between exon 3 and 4. (B) The dark blue color shows the 731 amino acid sequence of cGSN, which is consistent with pGSN and Gelsolin-3. Cyan color shows 24 and 11 different amino acid sequences in pGSN and Gelsolin-3, respectively, compared to cGSN. (C) GSN consist of six domains that are named G1-G6. There is a linker between G3 and G4 domain which is cleaved by caspase 3 producing N-terminal GSN and C-terminal GSN. Figure designed using BioRender. pGSN, plasma gelsolin; cGSN, cytoplasmic gelsolin.

Figure 2

Autocrine and paracrine action of pGSN. Exosomal pGSN derived from chemoresistant OVCA cells transforms chemosensitive cells into chemoresistant OVCA cells via the α5β1 integrins/FAK/Akt/HIF-1α axis (Paracrine action). In chemoresistant OVCA cells, exosomal pGSN increases the promoter region binding of HIF1α and enhances exosomal pGSN production. Thus, exosomal pGSN forms a positive feedback loop of pGSN production via α5β1 integrins/FAK/Akt/HIF-1α axis (Autocrine action). pGSN, plasma gelsolin; FAK, focal adhesion kinase; Akt, Ak strain transforming; HIF-1α, hypoxia-inducible factor 1-alpha. Figure designed using BioRender.

Figure 3

Apoptosis Regulation by pGSN. FLIP and ITCH form a complex with GSN in the chemosensitive OVCA cell. CDDP dissociates GSN from the GSN-FLIP-ITCH complex, leading to FLIP ubiquitination and degradation, caspase-8 and -3 activation, caspase-3-mediated GSN cleavage, and apoptosis. In chemo-resistant OVCA cells, CDDP does not alter the GSN-FLIP-ITCH interaction, attenuating its downstream effects. FLIP, Fas-associated death domain-like interleukin-1b-converting enzyme-like inhibitory protein; ITCH, Itchy E3 ubiquitin protein ligase; Ub, ubiquitin; GSN, gelsolin; CDDP, cis-Diamminedichloroplatinum; FADD, Fas associated via death domain; Casp8, caspase8. (Figure modified from Abedini et al., 2014 [69]. Figure designed using BioRender.

Figure 4

Immune dysfunction induced by pGSN. A chemoresistant ovarian cancer cell-derived exosomal pGSN causes CD8+ T cells to undergo apoptosis via caspase-3 activation. Apoptosis is not induced in CD4+ T cells by pGSN. CD4+ T cells secreted more IL-4, polarized to type 2 helper cells. IFNγ activates the IFNGR1/JAK/STAT1 pathway, decreasing the intracellular GSH levels. pGSN depletes CD8+ T cells and reduces IFNγ secretion. Thus, GSH production in ovarian cancer was increased and contributes to chemoresistance. Exosomal pGSN induces caspase-3 activation and apoptosis of M1 macrophages, which leads to decreased iNOS secretion. Furthermore, pGSN increases GSH content in ovarian cancer cells via decreased iNOS production in M1 macrophages, contributing to chemotherapy resistance. Abbreviations: pGSN, plasma gelsolin; IL-4, interleukin 4; IFNγ, Interferon gamma; IFNGR1, interferon gamma receptor 1; JAK, janus kinase; STAT1, signal transducer and activator of transcription 1; GSH, glutathione; iNOS, inducible nitric oxide synthase. Figure designed using BioRender.