{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T21:43:36Z","timestamp":1792100616205,"version":"4.4.0"},"reference-count":38,"publisher":"Begell House","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Crit Rev Immunol"],"published-print":{"date-parts":[[2025]]},"abstract":"<p>Immunotherapy has shown significant promise in the clinical management of prostate cancer (PCa), and prostaglandin E receptor 4 (EP4) is a key governing factor in PCa progression. However, the molecular mechanisms by which EP4 influences immunotherapy in PCa have yet to be elucidated. This investigation was designed to unravel the specific mechanisms through which EP4 affects the killing ability of CD8&lt;sup&gt;&amp;#43;&lt;\/sup&gt; T cells against PCa cells. Immunohistochemistry was utilized to assay the expression of EP4, programmed death ligand 1 (PD-L1), and CD8&lt;sup&gt;&amp;#43;&lt;\/sup&gt; T cell infiltration in tissue samples, and quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot (WB) were used to evaluate EP4 expression in cells. PCa cell lines with either EP4 knockdown or overexpression were co-cultured with CD8&lt;sup&gt;&amp;#43;&lt;\/sup&gt; T cells. Lactase dehydrogenase toxicity assays were employed to measure CD8&lt;sup&gt;&amp;#43;&lt;\/sup&gt;T cell killing ability, and ELISA was employed to measure interferon-gamma (IFN-&amp;gamma;), tumor necrosis factor-alpha (TNF-&amp;alpha;), and interleukin-2 (IL-2) levels. Expression of T cell exhaustion markers was detected by flow cytometry. Rescue experiments were conducted utilizing 3-methyladenine &amp;#91;a phosphoinositide 3-kinase (PI3K) inhibitor&amp;#93; and PD-L1 knockdown. The impact of EP4 overexpression on the PI3K\/AKT signaling pathway-mediated PD-L1 expression and its subsequent modulation of CD8&lt;sup&gt;&amp;#43;&lt;\/sup&gt; T cell killing ability against PCa cells was assessed through qRT-PCR, WB, flow cytometry, and immunofluorescence. EP4 exhibited a substantial upregulation in both PCa tissues and cells, displaying a positive correlation with PD-L1 expression and a converse negative correlation with the infiltration of CD8&lt;sup&gt;&amp;#43;&lt;\/sup&gt; T cells. Knockdown of EP4 expression inhibited CD8&lt;sup&gt;&amp;#43;&lt;\/sup&gt;  T cell exhaustion, enhanced CD8&lt;sup&gt;&amp;#43;&lt;\/sup&gt; T cell killing ability against PCa cells, increased the levels of IFN-&amp;gamma;, IL-2, and TNF-&amp;alpha;, and decreased PD-L1 expression. Conversely, EP4 overexpression resulted in opposite effects, but treatment with 3-methyladenine mitigated EP4-induced promotion of PD-L1, p-AKT, and t-AKT expression. Furthermore, the knockdown of PD-L1 mitigated the inhibitory impact of EP4 overexpression on the killing ability of CD8+ T cell and the levels of IFN-&amp;gamma;, IL-2, and TNF-&amp;alpha;, all while leaving the expression of p-AKT and t-AKT unaffected. EP4 was significantly overexpressed in PCa and activated PD-L1 expression via the PI3K\/AKT signaling pathway, thereby suppressing the activity of CD8&lt;sup&gt;&amp;#43;&lt;\/sup&gt; T cells.\n<\/p>","DOI":"10.1615\/critrevimmunol.2024052115","type":"journal-article","created":{"date-parts":[[2024,8,23]],"date-time":"2024-08-23T20:35:32Z","timestamp":1724445332000},"page":"1-13","source":"Crossref","is-referenced-by-count":4,"title":["The Overexpression of EP4 Attenuates the Killing Ability of CD8&amp;#43; T Cells against Prostate Cancer Cells through the PI3K\/AKT Signaling Pathway"],"prefix":"10.1615","volume":"45","author":[{"given":"Ying","family":"Zhou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lanying","family":"Zou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoping","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huichuan","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"613","reference":[{"key":"1","doi-asserted-by":"crossref","unstructured":"Meng M, Wu YC. 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