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ATRA promotes PD-L1 expression to control gastric cancer immune surveillance
Zhi-Lu Ma1, Yan-Li Ding1, Jing Jing1
1School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, 450001, China.
Abstract:
The vitamin A metabolite all-trans retinoic acid (ATRA) plays a key role in immune response, but effects of ATRA on cancer-associated immunity remains unclear. Previously, we have shown that ATRA regulates the expression of PD-L1 in gastric cancer (GC) cells. We herein reported the mechanism underlying ATRA-induced PD-L1 expression in GC cells and the effects of ATRA on cancer-associated immunosuppression in vitro and in vivo. ATRA enhanced PD-L1 expression through increasing its protein stability and protein synthesis, which was suppressed by JAK pan-inhibitor ruxolitinib (RUX) but enhanced in the combination with IFN-γ. In T-cell-mediated killing assay, the upregulation of PD-L1-induced by ATRA rendered GC cells strongly resistant to activated T-cell killing, which was reversed by RUX. In vivo, PD-L1 antibody restricted tumor growth, but ATRA antagonized PD-L1 antibody efficacy. Importantly, RUX not only inhibited the expression of PD-L1 induced by ATRA, but also resensitized GC cells to PD-L1 antibody. In conclusion, our study illustrated that ATRA attenuated the effect of PD-L1 blockade through upregulating PD-L1 and blocking PD-L1 expression is an important role for the generation of effective anti-tumor immune response in the combination of immunotherapy and chemotherapy or targeted therapy.
Insights
All-trans retinoic acid (ATRA) boosts PD-L1 expression in gastric cancer, hindering anti-tumor immunity. Ruxolitinib reverses this effect, restoring T-cell activity and enhancing immunotherapy efficacy.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- All-trans retinoic acid (ATRA) influences immune responses.
- The role of ATRA in cancer-associated immunity, specifically in gastric cancer (GC), is not fully understood.
- Previous studies indicated ATRA regulates PD-L1 expression in GC cells.
Purpose of the Study:
- To elucidate the mechanism of ATRA-induced PD-L1 expression in GC cells.
- To investigate the impact of ATRA on cancer-associated immunosuppression in vitro and in vivo.
- To evaluate the therapeutic potential of combining ATRA with PD-L1 blockade and JAK inhibitors.
Main Methods:
- Investigated ATRA's effect on PD-L1 expression and stability in GC cells.
- Utilized T-cell-mediated killing assays to assess immune evasion.
- Conducted in vivo studies using PD-L1 blockade and ruxolitinib (RUX).
- Examined the synergistic effects of ATRA, RUX, and IFN-γ on PD-L1 expression.
Main Results:
- ATRA enhanced PD-L1 expression by increasing protein stability and synthesis.
- ATRA-induced PD-L1 upregulation conferred resistance to T-cell killing, an effect reversed by RUX.
- In vivo, ATRA antagonized PD-L1 antibody efficacy in restricting tumor growth.
- RUX inhibited ATRA-induced PD-L1 expression and resensitized GC cells to PD-L1 antibody therapy.
Conclusions:
- ATRA attenuates PD-L1 blockade therapy by upregulating PD-L1.
- Blocking PD-L1 is crucial for effective anti-tumor immunity, especially when combined with immunotherapy, chemotherapy, or targeted therapy.
- Ruxolitinib shows potential in overcoming ATRA-mediated immunosuppression and enhancing immunotherapy outcomes in gastric cancer.
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