PD‐1/PD‐L1 blockade rescue exhausted CD8+ T cells in gastrointestinal stromal tumours via the PI3K/Akt/mTOR signalling pathway

Abstract

Objectives:Although targeted therapy has revolutionized the treatment of gastrointestinal stromal tumours (GIST), it is almost never curative in GIST, and resistance commonly develops. One potential strategy is to combine targeted therapy with immunotherapy. Materials and methods:We first studied Programmed cell death 1 ligand 1 (PD-L1) expression and tumour-infiltrating T cells (TILs) in GIST. IFN-γ was used to induce the upregulation of PD-L1 expression in GIST-882 cells, a well-known GIST cell line.CD8+ T-cell apoptosis was determined by flow cytometry. The PI3K/Akt/mTOR levels in CD8+ T cells were examined by Western blotting.Results: PD-L1 expression was an independent factor of poor prognosis in GIST and resulted in exhausted T cells in the TILs population or the blood. Then, we found that PD-L1 blockade alone could not increase tumour cell apoptosis in GIST. The apoptosis rate of CD8+ T cells was higher when T cells were cultured with PD-L1+ GIST-882 cells (GIST-882 cells with high PD-L1 expression) than when T cells were cultured with control GIST-882 cells. However, when the PD-L1 blockade was used, the apoptosis rates of the CD8+ T cells in the two groups became similar. Then, Western blotting showed the PI3K/Akt/mTOR levels of the CD8+ T cells rescued by the PD-1/ PD-L1 blockade were higher than those of the CD8+ T cells not treated with the PD-1/PD-L1 blockade.Conclusions: PD-L1 expression was an independent poor prognosis factor in GIST.PD-1/PD-L1 blockade rescued exhausted CD8+ T cells in GIST via the PI3K/Akt/ mTOR signalling pathway. In GIST, PD-1/PD-L1 not only function as predictive biomarkers but also improve current therapies as treatment targets.

PD-1-Mediated PI3K/Akt/mTOR, Caspase 9/Caspase 3 and ERK Pathways Are Involved in Regulating the Apoptosis and Proliferation of CD4+ and CD8+ T Cells During BVDV Infection in vitro

“…Activated PI3K/Akt/mTOR pathway can improve T lymphocyte metabolism, nutrient uptake and energy production, regulate cell cycle and apoptosis, and affect T lymphocyte activation and immune function (31)(32)(33)(34). Blocking the interaction between PD-1 and PD-L1 can reactivate PI3K/Akt/mTOR pathway and restore immune function of exhausted CD8 + T cells (35). In addition, the activation of the Ras/MEK/ERK pathway can promote cell protein synthesis and proliferation.…”

Prognostic Impact of PD-1 and Tim-3 Expression in Tumor Tissue in Stage I-III Colorectal Cancer

“…In addition, Tim-3 is associated with immunotherapy of metastatic renal cell carcinoma [48]. PD-1 can inhibit the proliferation of T cells and the production of related cytokines by the PI3K/AKT signaling pathway through immune cell fatigue [49]. When the pathways of PD-1/PD-L1 are activated, cancer cells could evade the immune response and continue to proliferate [50].…”

Tumor-associated tertiary lymphoid structure predicts postoperative outcomes in patients with primary gastrointestinal stromal tumors

“…47 Tumors with high TILs are thought to be a good predictor for sensitivity to immune checkpoint therapies, as they could promote in situ anti-tumor response and reverse immune escape mechanisms. 24 Therapies to block PD-1 and PD-L1, which could rescue exhausted CD8 + T cells via the PI3 K/Akt/mTOR signaling pathway, 48 had shown promising results in combination with imatinib for treating GIST. 49 Depending on CD8 + T cells, the combination of anti-CD40 drugs and imatinib has also been an effective strategy for treating GIST patients.…”