Role of NLRP3, IL-18, and IL-18R signaling for exhaustion mechanisms in the interaction of myeloid cells and T cells in a pancreatic carcinoma model
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Pancreatic cancer is one of the most malignant and lethal tumor entities. Due to diagnosis at late stages and its aggressiveness, many patients with pancreatic cancer face a poor prognosis. Low immunogenicity, low antigenicity, and drug resistance further complicate the treatment of this cancer. Immunosuppressive cell populations within the tumor alter the microenvironment in a manner that renders it highly immune-avoidant. This results in a dysregulation of crosstalk between T cells and macrophages facilitating the progression of cancer. In pancreatic cancer models, a dysfunctional state of T cells is promoted by IL-18R-mediated signaling and associated with T cell exhaustion. IL-18 is a pro-inflammatory cytokine processed by the NLRP3 inflammasome. This study investigated the potential role of the myeloid NLRP3 inflammasome for IL-18R-mediated signaling in T cell exhaustion. Genetic depletion and pharmacological inhibition of NLRP3 were utilized to explore the functionality of the inflammasome after in vitro activation in BMDMs. Treatment of BMDMs with LPS and nigericin induced the inflammasome, as indicated by the production of IL-18 and IL-1β. Notably, NLRP3-derived IL-1β promoted the upregulation of PD-L1 on the cell surface. Accordingly, analysis of TAMs in the TME of mice lacking NLRP3 revealed reduced PD-L1 expression. An in vitro co-culture model was used to analyze the interactions between T cells and macrophages during the early development of T cell exhaustion. Prominent markers for co-inhibitory checkpoint receptors were used to investigate the effect of NLRP3-mediated signaling for exhaustion in CD8+ T cells. The proportion of T cells expressing PD-1 and TIM-3 displayed no difference when cocultured with the M1- or M2-like subset. However, a loss of effector function was observed in T cells co-cultured with M2-like BMDMs, as indicated by impaired TNF production. Employing a CRISPR/Cas9 knockout of NLRP3 in a tumor cell line, tumor growth and the composition of the TME in host mice were analyzed. Tumors lacking NLRP3 showed repressed growth and progression. Moreover, elevated infiltration of CD8+ T cells and reduced percentages of PD-1+TIM-3+ cells were observed in the knockout tumors. Finally, these findings suggest that the NLRP3 inflammasome plays a dual role in regulating immunosuppressive tumor milieu. Through T cell-intrinsic effects of IL-18R signaling and the upregulation of PD-L1, the inflammasome contributes intratumoral T cell exhaustion.
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This item has been published with the following license: In Copyright