Activation of PGE2/EP2 and PGE2/EP4 signaling pathways positively regulate the level of PD‑1 in infiltrating CD8+ T cells in patients with lung cancer

Abstract

Abstract. The present study aimed to identify the level of programmed death-1 (PD-1) expression in infiltrating cluster of differentiation (CD)4 + and CD8 + T cells isolated from lung cancer tissues, and investigated whether the level of PD-1 expression may be directly regulated by lung cancer cells via prostaglandin E2 (PGE2)-associated signaling pathways in patients with lung cancer. A total of 75 patients with lung cancer were enrolled in the present study. The percentage of infiltrating CD4 + and CD8 + T cells was determined by flow cytometry. ELISA was performed to evaluate the concentration of PGE2 in lung cancer tissue homogenate. The correlation between PGE2 and PD-1 expression levels in CD8 + T cells was assessed by Spearman's rank correlation test. The expression levels of PD-1 and PGE2 receptors were determined by reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. The level of PD-1 expression in infiltrating CD8 + T cells was gradually increased as the stage of lung cancer increased. The level of PD-1 expression was also positively associated with the concentration of PGE2 in lung cancer tissues. Furthermore, the level of PD-1 expression was closely associated with the PGE2/EP2 and PGE2/EP4 signaling pathways. The activation of PGE2-associated EP2-and EP4-pathways may positively regulate the level of PD-1 in infiltrating CD8 + T cells, which results in immune tolerance in the lung cancer microenvironment.

Is There an Interplay between Immune Checkpoint Inhibitors, Thromboprophylactic Treatments and Thromboembolic Events? Mechanisms and Impact in Non-Small Cell Lung Cancer Patients

“…In our series, the increased TE risk associated with smoking status and high PD-L1 expression agreed with both of these hypotheses, as these factors may promote atherogenesis, but also contribute to better patient outcome during ICI treatment. In particular, PGE2 concentration in lung cancer tissue significantly correlates with PD-1 expression on CD8 + tumor infiltrating lymphocytes, suggesting PGE2 related inflammation as a possible link between TE events and T-cells' exhaustion [41]. Furthermore, we observed that the development of TE events during ICIs is an independent prognostic factor associated with worse survival when considered as a time dependent variable [39].…”

“…However, the effect of COX-2/mPGES1 pathway inhibition on PD-L1 expression and the impact of this modulation on ICIs efficacy are still controversial. While some in vitro studies reported that COX-2 inhibition reduced the expression of PD-L1 [24,49,51] and may potentially reduce exhaustion of T-cells in the tumor microenvironment [41], others highlighted that treatment with celecoxib did not affect PD-L1 levels in melanoma and NSCLC cells [22,52], and PD-L1 staining was also shown to be dramatically greater in mPGES1 knock out derived tumor tissues compared to controls [22]. Furthermore, the effect of other COXi (e.g., nonsteroidal anti-inflammatory drugs and paracetamol) on ICI treatment outcome might differ from that of low dose ASA due to the different COX selectivity and reversibility of the binding.…”

The Interaction of N-Acetylcysteine and Serum Transferrin Promotes Bacterial Biofilm Formation

“…Many in vitro studies have shown the ability of NAC to prevent biofilm formation by a variety of microorganisms, including a variety of Gram-positive and Gram-negative bacteria, as well as some yeasts [9]. In addition to its direct antibacterial effect, NAC also inhibits the production of extracellular polysaccharide, reduces bacterial adherence, and promotes dispersal of mature biofilms [10, 11, 14, 31]. However, the mechanisms by which NAC prevents biofilm formation are complex and largely unknown.…”

The COX2 Effector Microsomal PGE2 Synthase 1 is a Regulator of Immunosuppression in Cutaneous Melanoma

“…PGE2 acting through EP2 and EP4 prostanoid receptors is a key inducer of T cell cAMP levels (34). The activation of the EP2 and EP4 pathways by PGE2 may also positively regulate the level of PD-1 in infiltrating CD8 þ T cells, which results in immune tolerance (35). Indirect PGE2 effects, in contrast, can involve a number of immune cell factors, including MDSC, DCs, natural killer cells, and macrophages.…”