Kaiyuan Wang1,2, Jian Wang2, Ting Liu2, Wenwen Yu2, Nan Dong2, Chen Zhang2, Wenbin Xia3, Feng Wei2, Lili Yang2, Xiubao Ren2,4. 1. Department of Anesthesiology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin 300060, China. 2. Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin 300060, China. 3. Department of Cancer Biobank, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin 300060, China. 4. Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin 300060, China.
Abstract
Objective: Patients with cancer pain are highly dependent on morphine analgesia, but studies have shown a negative correlation between morphine demand and patient outcomes. The long-term use of morphine may result in abnormally elevated serum morphine-3-glucuronide (M3G) levels. Hence, the effects of M3G on tumor progression are worth studying. Methods: The effects of M3G on PD-L1 expressions in human non-small cell lung cancer (NSCLC) cell lines were first evaluated. Activation of TLR4 downstream pathways after M3G treatment was then determined by Western blot. The effects of M3G on human cytotoxic T lymphocytes (CTL) cytotoxicity and INF-γ release was also detected. Finally, the LLC murine lung adenocarcinoma cell line were used to establish a murine lung cancer model, and the effects of M3G on tumor growth and metastasis were determined. Results: M3G promoted the expressions of PD-L1 in the A549 and H1299 cell lines in a TLR4-dependent manner (P < 0.05). M3G activated the PI3K and the NFκB signaling pathways, and this effect was antagonized by a TLR4 pathway inhibitor. A PI3K pathway inhibitor reversed the M3G-mediated PD-L1 upregulation. M3G inhibited the cytotoxicity of CTL on A549 cells and decreased the level of INF-γ. Repeated M3G intraperitoneal injections promoted LLC tumor growth and lung metastasis through the upregulation of tumor expressed PD-L1 and the reduction of CTL in the tumor microenvironment. Conclusions: M3G specifically activated TLR4 in NSCLC cells and upregulated PD-L1 expression through the PI3K signaling pathway, thereby inhibiting CTL cytotoxicity and finally promoting tumor immune escape. Copyright:
Objective: Patients with cancer pain are highly dependent on morphine analgesia, but studies have shown a negative correlation between morphine demand and patient outcomes. The long-term use of morphine may result in abnormally elevated serum morphine-3-glucuronide (M3G) levels. Hence, the effects of M3G on tumor progression are worth studying. Methods: The effects of M3G on PD-L1 expressions in human non-small cell lung cancer (NSCLC) cell lines were first evaluated. Activation of TLR4 downstream pathways after M3G treatment was then determined by Western blot. The effects of M3G on human cytotoxic T lymphocytes (CTL) cytotoxicity and INF-γ release was also detected. Finally, the LLC murine lung adenocarcinoma cell line were used to establish a murine lung cancer model, and the effects of M3G on tumor growth and metastasis were determined. Results: M3G promoted the expressions of PD-L1 in the A549 and H1299 cell lines in a TLR4-dependent manner (P < 0.05). M3G activated the PI3K and the NFκB signaling pathways, and this effect was antagonized by a TLR4 pathway inhibitor. A PI3K pathway inhibitor reversed the M3G-mediated PD-L1 upregulation. M3G inhibited the cytotoxicity of CTL on A549 cells and decreased the level of INF-γ. Repeated M3G intraperitoneal injections promoted LLC tumor growth and lung metastasis through the upregulation of tumor expressed PD-L1 and the reduction of CTL in the tumor microenvironment. Conclusions: M3G specifically activated TLR4 in NSCLC cells and upregulated PD-L1 expression through the PI3K signaling pathway, thereby inhibiting CTL cytotoxicity and finally promoting tumor immune escape. Copyright:
Authors: Elizabeth A Mittendorf; Anne V Philips; Funda Meric-Bernstam; Na Qiao; Yun Wu; Susan Harrington; Xiaoping Su; Ying Wang; Ana M Gonzalez-Angulo; Argun Akcakanat; Akhil Chawla; Michael Curran; Patrick Hwu; Padmanee Sharma; Jennifer K Litton; Jeffrey J Molldrem; Gheath Alatrash Journal: Cancer Immunol Res Date: 2014-01-10 Impact factor: 11.151
Authors: Michal Marzec; Qian Zhang; Ami Goradia; Puthiyaveettil N Raghunath; Xiaobin Liu; Michele Paessler; Hong Yi Wang; Maria Wysocka; Mangeng Cheng; Bruce A Ruggeri; Mariusz A Wasik Journal: Proc Natl Acad Sci U S A Date: 2008-12-16 Impact factor: 11.205
Authors: D P Maher; W Wong; P F White; R McKenna; H Rosner; B Shamloo; C Louy; R Wender; R Yumul; V Zhang Journal: Br J Anaesth Date: 2014-07-09 Impact factor: 9.166
Authors: Juan Moreno-Rubio; Santiago Ponce; Rosa Álvarez; María Eugenia Olmedo; Sandra Falagan; Xabier Mielgo; Fátima Navarro; Patricia Cruz; Luis Cabezón-Gutiérrez; Carlos Aguado; Gonzalo Colmenarejo; Marta Muñoz-Fernández de Leglaria; Ana Belén Enguita; María Cebollero; Amparo Benito; Isabel Alemany; Carolina Del Castillo; Ricardo Ramos; Ana Ramírez de Molina; Enrique Casado; Maria Sereno Journal: Cancer Biol Med Date: 2020-05-15 Impact factor: 4.248