期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 131, 期 8, 页码 -出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI139434
关键词
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资金
- 2019 AACR-Pfizer Immuno-oncology Research Fellowship [19-40-49-JIAN]
- Breast Cancer Research Foundation [BCRF-19-070]
- MD Anderson National Cancer Institute Cancer Center support grant, National Cancer Institute (NCI) [CCSG CA016672]
- Cancer Prevention and Research Institute of Texas [RP160710]
- National Breast Cancer Foundation Inc.
- Patel Memorial Breast Cancer Endowment Fund
- University of Texas MD Anderson-China Medical University and Hospital Sister Institution Network Fund
- Center for Biological Pathways
Research shows that tumors with high TYRO3 expression exhibit resistance to PD-1/PD-L1 therapy by inhibiting tumor cell ferroptosis and altering the tumor microenvironment. Inhibition of TYRO3 promotes tumor ferroptosis and sensitizes resistant tumors to PD-1 therapy. This suggests that TYRO3 could be a predictive biomarker for patient selection and a promising therapeutic target to overcome resistance to PD-1/PD-L1 therapy.
Immune checkpoint blockade therapy has demonstrated promising clinical outcomes for multiple cancer types. However, the emergence of resistance as well as inadequate biomarkers for patient stratification have largely limited the clinical benefits. Here, we showed that tumors with high TYRO3 expression exhibited anti?programmed cell death protein 1/programmed death ligand 1 (anti?PD-1/PD-L1) resistance in a syngeneic mouse model and in patients who received anti?PD-1/PD-L1 therapy. Mechanistically, TYRO3 inhibited tumor cell ferroptosis triggered by anti?PD-1/PD-L1 and facilitated the development of a protumor microenvironment by reducing the M1/M2 macrophage ratio, resulting in resistance to anti?PD-1/PD-L1 therapy. Inhibition of TYRO3 promoted tumor ferroptosis and sensitized resistant tumors to anti?PD-1 therapy. Collectively, our findings suggest that TYRO3 could serve as a predictive biomarker for patient selection and a promising therapeutic target to overcome anti?PD-1/PD-L1 resistance.
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