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

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

doi:10.1172/jci139434

Cited by 179 publications

(132 citation statements)

References 35 publications

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“…Immunotherapy synergizing with radiotherapy can induce ferroptosis and T-cell immunity in tumor ( Lang et al, 2019 ). By limiting immunity and ferroptosis, TYRO3 can induce anti-PD-1/PD-L1 therapy resistance in tumors ( Jiang et al, 2021 ). A critical molecule relationship for bridging ferroptosis and immunotherapy was found to identify eligible patients for the ferroptosis-induction therapy combined with immunotherapy in clear cell renal carcinoma ( Mou et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

A Ferroptosis-Related Gene Model Predicts Prognosis and Immune Microenvironment for Cutaneous Melanoma

Chen

2021

Front. Genet.

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BackgroundCutaneous melanoma is a common but aggressive tumor. Ferroptosis is a recently discovered cell death with important roles in tumor biology. Nevertheless, the prognostic power of ferroptosis-linked genes remained unclear in cutaneous melanoma.MethodsCutaneous melanoma patients of TCGA (The Cancer Genome Atlas) were taken as the training cohort while GSE65904 and GSE22153 as the validation cohorts. Multifactor Cox regression model was used to build a prognostic model, and the performance of the model was assessed. Functional enrichment and immune infiltration analysis were used to clarify the mechanisms.ResultsA five ferroptosis-linked gene predictive model was developed. ALOX5 and GCH1 were illustrated as independent predictive factors. Functional assessment showed enriched immune-linked cascades. Immune infiltrating analysis exhibited the distinct immune microenvironment.ConclusionHerein, a novel ferroptosis-related gene prognostic model was built in cutaneous melanoma. This model could be used for prognostic prediction, and maybe helpful for the targeted and immunotherapies.

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Section: Discussionmentioning

confidence: 99%

A Ferroptosis-Related Gene Model Predicts Prognosis and Immune Microenvironment for Cutaneous Melanoma

Chen

2021

Front. Genet.

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“…Cancer cells coopt regulatory circuits evolutionarily generated to maintain tissue homeostasis in order to resist growth under immunological pressure and promote tumor immune escape. Accordingly, altered expression and signaling of TAMRTK is involved in tumor progression ( 298 , 300 ) and inhibition of TYRO3 conferred responsiveness to ICI because TYRO3 promotes the development and accumulation of suppressive TAM ( 345 ). Also, blockade of MerTK on TAM triggered P2X7R-dependent activation of STING by tumor-derived cGAMP, stimulated a type I IFN response that reshaped the TME, promoted T cell activation and synergized with ICI, contributing to an efficient antitumor immunity ( 346 ).…”

Section: Rational Design Of Combination Therapies That Target the Nkg2d-nkg2dl Axismentioning

confidence: 99%

Leveraging NKG2D Ligands in Immuno-Oncology

2021

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Immune checkpoint inhibitors (ICI) revolutionized the field of immuno-oncology and opened new avenues towards the development of novel assets to achieve durable immune control of cancer. Yet, the presence of tumor immune evasion mechanisms represents a challenge for the development of efficient treatment options. Therefore, combination therapies are taking the center of the stage in immuno-oncology. Such combination therapies should boost anti-tumor immune responses and/or target tumor immune escape mechanisms, especially those created by major players in the tumor microenvironment (TME) such as tumor-associated macrophages (TAM). Natural killer (NK) cells were recently positioned at the forefront of many immunotherapy strategies, and several new approaches are being designed to fully exploit NK cell antitumor potential. One of the most relevant NK cell-activating receptors is NKG2D, a receptor that recognizes 8 different NKG2D ligands (NKG2DL), including MICA and MICB. MICA and MICB are poorly expressed on normal cells but become upregulated on the surface of damaged, transformed or infected cells as a result of post-transcriptional or post-translational mechanisms and intracellular pathways. Their engagement of NKG2D triggers NK cell effector functions. Also, MICA/B are polymorphic and such polymorphism affects functional responses through regulation of their cell-surface expression, intracellular trafficking, shedding of soluble immunosuppressive isoforms, or the affinity of NKG2D interaction. Although immunotherapeutic approaches that target the NKG2D-NKG2DL axis are under investigation, several tumor immune escape mechanisms account for reduced cell surface expression of NKG2DL and contribute to tumor immune escape. Also, NKG2DL polymorphism determines functional NKG2D-dependent responses, thus representing an additional challenge for leveraging NKG2DL in immuno-oncology. In this review, we discuss strategies to boost MICA/B expression and/or inhibit their shedding and propose that combination strategies that target MICA/B with antibodies and strategies aimed at promoting their upregulation on tumor cells or at reprograming TAM into pro-inflammatory macrophages and remodeling of the TME, emerge as frontrunners in immuno-oncology because they may unleash the antitumor effector functions of NK cells and cytotoxic CD8 T cells (CTL). Pursuing several of these pipelines might lead to innovative modalities of immunotherapy for the treatment of a wide range of cancer patients.

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“…Lee et al reported that erastin induces TNBC cell ferroptosis by inhibiting system xc − and depleting GPX4 levels, despite the resistance against oxidative stress [ 50 ]. Jiang et al reported that tyrosine-protein kinase receptor 3 (TYRO3) plays a negative role on tumor ferroptosis, and induces resistance to anti-PD1/PD-L1 treatment [ 32 ]. TYRO3 overexpression activates the PI3K/AKT pathway to increase NRF2 transcriptional activity that is responsible for the transcription of ferroptosis-inhibitory genes, including SLC3A2, SLC7A11, FTL, FTH1, GPX4, SLC40A1, and biliverdin reductase A/B (BLVRA/B) [ 32 ].…”

Section: Inducing Ferroptosis By Inhibiting Antioxidant Defensementioning

confidence: 99%

“…Jiang et al reported that tyrosine-protein kinase receptor 3 (TYRO3) plays a negative role on tumor ferroptosis, and induces resistance to anti-PD1/PD-L1 treatment [ 32 ]. TYRO3 overexpression activates the PI3K/AKT pathway to increase NRF2 transcriptional activity that is responsible for the transcription of ferroptosis-inhibitory genes, including SLC3A2, SLC7A11, FTL, FTH1, GPX4, SLC40A1, and biliverdin reductase A/B (BLVRA/B) [ 32 ]. Further study showed that the TYRO3 inhibitor, LDC1267, can elicit ferroptosis and potentiate immunotherapy in a 4T1 BC cell inoculation mouse model [ 32 ].…”

Section: Inducing Ferroptosis By Inhibiting Antioxidant Defensementioning

confidence: 99%

“…A growing body of study has led to the identification of an intricate signaling pathway that controls ferroptosis by inducing iron accumulation and lipid peroxidation or perturbing the antioxidant defensive system. Importantly, recent reports have revealed that cancer cells which are resistant to conventional therapy or harbor a propensity to metastasize are vulnerable to ferroptosis, and that immunotherapeutic effects can be potentiated by ferroptosis [ 32 , 33 , 34 , 35 ]. In light of this, we herein aimed to review the latest research on ferroptosis to further the understanding of its pathogenesis and to propose new targets for the treatment of BC ( Table 2 ).…”

Section: Introductionmentioning

confidence: 99%

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The Evolving Role of Ferroptosis in Breast Cancer: Translational Implications Present and Future

Lin

Chang

et al. 2021

Cancers

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Breast cancer (BC) is the most common malignancy among women worldwide. The discovery of regulated cell death processes has enabled advances in the treatment of BC. In the past decade, ferroptosis, a new form of iron-dependent regulated cell death caused by excessive lipid peroxidation has been implicated in the development and therapeutic responses of BC. Intriguingly, the induction of ferroptosis acts to suppress conventional therapy-resistant cells, and to potentiate the effects of immunotherapy. As such, pharmacological or genetic modulation targeting ferroptosis holds great potential for the treatment of drug-resistant cancers. In this review, we present a critical analysis of the current understanding of the molecular mechanisms and regulatory networks involved in ferroptosis, the potential physiological functions of ferroptosis in tumor suppression, its potential in therapeutic targeting, and explore recent advances in the development of therapeutic strategies for BC.

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

Cited by 179 publications

References 35 publications

A Ferroptosis-Related Gene Model Predicts Prognosis and Immune Microenvironment for Cutaneous Melanoma

A Ferroptosis-Related Gene Model Predicts Prognosis and Immune Microenvironment for Cutaneous Melanoma

Leveraging NKG2D Ligands in Immuno-Oncology

The Evolving Role of Ferroptosis in Breast Cancer: Translational Implications Present and Future

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