Polyfunctional T-cell responses are disrupted by the XXXX ascites environment and only partially restored by clinically relevant cytokines.

@entity43 @entity1 @entity3220 @entity404 @entity1261 @entity4666 @entity1356 @entity5 @entity310 @entity2841 @entity1193 @entity12868 @entity15787 @entity4155 @entity8923 @entity379 @entity540 @entity1199 @entity405 @entity10557
BACKGROUND: Host T-cell responses are associated with favorable outcomes in @entity43 ( @entity43 ), but it remains unclear how best to promote these responses in @entity1 . Toward this goal, we evaluated a panel of clinically relevant cytokines for the ability to enhance multiple T-cell effector functions (polyfunctionality) in the native @entity5 environment. METHODOLOGY/PRINCIPAL FINDINGS: Experiments were performed with resident @entity405 + and @entity404 + T cells in bulk ascites cell preparations from high-grade serous @entity43 @entity1 . T cells were stimulated with a-CD3 in the presence of 100% autologous ascites fluid with or without exogenous @entity1199 , IL-12, @entity8923 or @entity15787 , alone or in combination. T-cell proliferation (Ki-67) and function ( @entity379 , @entity310 , @entity1199 , @entity12868 , and @entity3220 expression) were assessed by multi-parameter flow cytometry. In parallel, 27 cytokines were measured in culture supernatants. While ascites fluid had variable effects on @entity405 + and @entity404 + T-cell proliferation, it inhibited T-cell function in most @entity1 samples, with @entity3220 , @entity379 , and @entity12868 showing the greatest inhibition. This was accompanied by reduced levels of @entity1356 , @entity1193 , @entity4666 , @entity4155 , @entity1261 , @entity2841 , @entity10557 , PDGF-bb, and @entity540 in culture supernatants. T-cell proliferation was enhanced by exogenous @entity1199 , but other T-cell functions were largely unaffected by single cytokines. The combination of @entity1199 with cytokines engaging complementary signaling pathways, in particular IL-12 and @entity8923 , enhanced expression of @entity379 , @entity310 , and @entity12868 in all @entity1 samples by promoting polyfunctional T-cell responses. Despite this, other functional parameters generally remained inhibited. CONCLUSIONS/SIGNIFICANCE: The @entity43 ascites environment disrupts multiple T-cell functions, and exogenous cytokines engaging diverse signaling pathways only partially reverse these effects. Our results may explain the limited efficacy of cytokine therapies for @entity43 to date. Full restoration of T-cell function will require activation of signaling pathways beyond those engaged by @entity1199 , IL-12, @entity8923 , and @entity15787 .
