Indoleamine 2, 3-dioxygenase Regulates the Differentiation of T Lymphocytes to Promote the Growth of Gastric Cancer Cells through the PI3K/Akt/mTOR Pathway

To investigate the regulatory mechanism of indoleamine 2, 3-dioxygenase (IDO) in T lymphocyte differentiation and its role in promoting the growth of gastric Cancer (GC) cells through the PI3K/Akt/mTOR pathway. GC cell lines (MFC and NCI-N87) and PBMC cells were co-cultured and IDO Inhibitor 1-methyl-tryptophan (1-MT) was added. The proliferation was detected by CCK-8, the Apoptosis was detected by flow cytometry, and the contents of TNF-α, IL-1β, IL-6, IL-8, and INF-γ were detected by ELISA. The expression levels of PI3K, p-PI3K, Akt, p-Akt, mTOR, and p-mTOR were tested using Western blot, and the proportion of CD4⁺/CD8⁺, CD4⁺CD25⁺Foxp3⁺Treg cells was detected by flow cytometry. C57BL/6 mice were used to establish the MFC GC mouse model and treated with 1-MT. The changes in body weight and tumor diameter were measured. Ki-67, CD4⁺, CD8⁺, and CD25⁺ expressions were detected by immunohistochemistry. IDO promoted the proliferation of MFC and NCI-N87 cells, inhibited Apoptosis, and decreased the levels of TNF-α, IL-1β, IL-6, IL-8, and INF-γ in the supernatant after co-culture with BPMC. The expressions of p-AKT, p-mTOR, and p-PI3K increased after 1-MT treatment. The proportion of CD4⁺/CD8⁺ cells was increased and the proportion of Treg cells was decreased in PBMC cells after the addition of 1-MT. Overexpression of IDO suppressed T cells differentiation by inhibiting the PI3K/Akt/mTOR pathway. In vivo, 1-MT treatment reduced the tumor size and weight, increased CD4⁺ and CD8⁺ positive area proportion, and decreased Ki-67 and CD25⁺ positive area proportion. Co-culture of GC cells and immune cells promotes the proliferation of GC cells and inhibits Apoptosis, which can be reversed by 1-MT. IDO may suppress the proliferation of T lymphocyte through inhibiting the PI3K/Akt/mTOR signaling pathway. This provides new evidence for the potential of exploiting IDO inhibitors for GC treatment.

Gastric cancer; Immunotherapy; Indoleamine 2, 3-dioxygenase; PI3K/Akt/mTOR; T lymphocytes; Tumor microenvironment.