Molecular mechanisms of malignant ascites-induced immunosuppression and options for nanoparticle-based therapeutic interventions

Ovarian cancer is the 5th most common cause of cancer death in women and remains one of the deadliest female malignancies. Due to the vague symptoms, it is often detected after peritoneal carcinomatosis and after ascites has developed. Malignant ascites is a fluidic immunosuppressive microenvironment that promotes disease progression. However, the exact mechanisms remain poorly understood. To explore the immunosuppressive mechanisms operative in malignant ascites, in manuscript 1, we developed an in vitro model of NK and T cell interaction with ovarian cancer cells in the presence of patient-derived ascites. We found that ascites inhibited various effector functions such as NK cell degranulation, tumor lysis, cytokine secretion, and calcium signaling. Using potentiometry, we identified imbalanced electrolytes as potential candidates causing immunosuppression. In mechanistic studies high sodium content significantly suppressed NK and T cell signaling and activation. Excess sodium also caused changes in electrolyte channels' protein transcription and expression. Selected sodium ion channel inhibitors restored calcium flux, conjugation to target cells, degranulation, and phosphorylation of signaling molecules in NK cells. These data suggest a novel electrolyte-based immunosuppression mechanism in malignant peritoneal ascites. Therapeutic inhibition of sodium channels could restore effector functions in ascites and other similarly imbalanced environments. Functionalized nanoparticles are versatile tools that can be used to therapeutically target such immunosuppressive cancer environments. Calcium phosphate nanoparticles (CaP-NPs) are biodegradable and biomimicking vehicles that can be functionalized with different moieties for imaging, targeting, and therapy. However, a prerequisite for such nanotherapy is that the therapeutic particles do not impair intrinsic or induced anti-tumor effector functions of immune cells. To test this, in manuscript 2, we utilized an in vitro system of NK and ovarian cancer cells. In this coculture system, CaP-NP addition did not impair conjugation or degranulation. Properly sonicated CaP-NPs did not induce unspecific degranulation or cytokine production. These properties indicate that our nanoparticle preparation is safe for biomedical applications. Furthermore, Cetuximab coupled to CaP-NP surface retained its ADCC-inducing properties and enabled EGFR targeting. Successful tumor cell transfection was detected via nanoparticle-coupled FITC. Considering the CaP-NPs biocompatibility and ease of uptake, they could be used for targeted delivery of therapeutics designed to counter imbalanced electrolytes of TME.



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