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TYRO3 induces anti–PD-1/PD-L1 therapy resistance by limiting innate immunity and tumoral ferroptosis
Zhou Jiang, … , Dihua Yu, Mien-Chie Hung
Zhou Jiang, … , Dihua Yu, Mien-Chie Hung
Published April 15, 2021
Citation Information: J Clin Invest. 2021;131(8):e139434. https://doi.org/10.1172/JCI139434.
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Research Article Cell biology Oncology Article has an altmetric score of 5

TYRO3 induces anti–PD-1/PD-L1 therapy resistance by limiting innate immunity and tumoral ferroptosis

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Abstract

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.

Authors

Zhou Jiang, Seung-Oe Lim, Meisi Yan, Jennifer L. Hsu, Jun Yao, Yongkun Wei, Shih-Shin Chang, Hirohito Yamaguchi, Heng-Huan Lee, Baozhen Ke, Jung-Mao Hsu, Li-Chuan Chan, Gabriel N. Hortobagyi, Liuqing Yang, Chunru Lin, Dihua Yu, Mien-Chie Hung

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Figure 5

Inhibition of TYRO3 enhances ferroptosis and sensitizes resistant tumors to anti–mPD-1 therapy.

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Inhibition of TYRO3 enhances ferroptosis and sensitizes resistant tumors...
(A) Immunoprecipitation followed by Western blot analysis of TYRO3 tyrosine phosphorylation (p-Tyr) in 4T1 cells treated with the TYRO3 inhibitor (TYRO3i) LDC1267 (2.5 μM, 2.5 hours) or control (DMSO), and in the presence or absence of Gas6 (100 nM, 30 minutes). TYRO3 served as a loading control.. (B) Percentage of 7-AAD+ cells in 4T1-R or Tyro3−/− cells treated with 0, 1, 2.5, and 5 μM LDC1267 for 24 hours (n = 3). NS P = 0.94, ****P < 0.0001, NS P = 0.87, NS P = 0.19, and NS P = 0.09, by 2-way ANOVA. (C) Relative lipid ROS in 4T1-R or Tyro3−/− cells treated with 5 μM LDC1267 for 12 hours (n = 3). ****P < 0.0001 and NS P = 0.16, by 2-tailed, unpaired Student’s t test. (D) Schematic showing the treatment schedule to evaluate the combination of LDC1267 and anti–mPD-1 treatment in mice. LDC1267 was intraperitoneally injected into mice starting on the third day after tumor inoculation for a total of 2 rounds, with 5 treatments for each round. Anti–mPD-1 was intraperitoneally injected into mice for a total of 5 treatments. (E) Growth of 4T1-R tumors in mice that were given anti–mPD-1, LDC1267, or their combination. IgG treatment served as a control (n = 10 mice per group). ****P < 0.0001 and **P = 0.0039, by 2-way ANOVA. Data are presented as the mean ± SEM. (F) Survival of mice in each group. ****P < 0.0001, by 2-sided log-rank test (TYRO3i plus anti–PD-1 versus anti–PD-1 alone). (G) Indicators of liver and kidney function in mice. The normal range for BUN, (H) AST, and (I) ALT are indicated by the dashed lines (n = 3 mice per group). (J) Schematic of the proposed model showing that TYRO3 inhibits tumor ferroptosis and supports a protumor TME by reducing the ratio of M1/M2 macrophages, thus promoting anti–PD-1 therapy resistance.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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