AXL targeting restores PD-1 blockade sensitivity of STK11/LKB1 mutant NSCLC through expansion of TCF1+ CD8 T cells

Li, Huiyu; Liu, Zhida; Liu, Longchao; Zhang, Hongyi; Han, Chuanhui; Girard, Luc; Park, Hyunsil; Zhang, Anli; Dong, Chunbo; Ye, Jianfeng; Rayford, Austin; Peyton, Michael; Li, Xiaoguang; Avila, Kimberley; Cao, Xuezhi; Hu, Shuiqing; Alam, Md Maksudul; Akbay, Esra A.; Solis, Luisa M.; Behrens, Carmen; Hernandez-Ruiz, Sharia; Lü, Wei; Wistuba, Ignacio I.; Heymach, John V.; Chisamore, Michael; Micklem, David; Gabra, Hani; Gausdal, Gro; Lorens, James B.; Li, Bo; Fu, Yang–Xin; Minna, John D.; Brekken, Rolf A.

doi:10.1016/j.xcrm.2022.100554

Cited by 43 publications

(34 citation statements)

References 68 publications

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“…177 In addition, type I IFNs are essential for expansion of stem-like T cells. 178 One of the type I IFNs, IFN-α, has been widely explored in the clinic for treating different types of cancer, such as hematologic cancers, melanoma, and other advanced metastatic diseases. 175,179,180 Type II IFN, known as IFN-γ, also promotes antiviral immunity and is critical in coordinating the innate and adaptive immune response.…”

Section: Type I Ifn and Sting Agonistsmentioning

confidence: 99%

“…Type I IFNs can also contribute to the activation and maturation of DCs, further benefiting antigen presentation and T cell priming 177 . In addition, type I IFNs are essential for expansion of stem‐like T cells 178 . One of the type I IFNs, IFN‐α, has been widely explored in the clinic for treating different types of cancer, such as hematologic cancers, melanoma, and other advanced metastatic diseases 175,179,180 .…”

Section: Antiangiogenic Therapy In Combination With Immunotherapymentioning

confidence: 99%

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Direct and indirect regulation of the tumor immune microenvironment by VEGF

Zhang

Brekken

2022

Journal of Leukocyte Biology

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Vascular endothelial growth factor-A (VEGF) is the predominant angiogenic factor that is expressed in solid tumors. Besides its critical function in mediating tumor angiogenesis, multiple studies have demonstrated that VEGF also contributes to tumor immunosuppression. VEGF interferes with immune cell trafficking indirectly by promoting a vascular immune barrier through VEGF receptor (VEGFR) activity on endothelial cells. However, VEGFRs are also expressed on multiple immune cell types, including T cells (effector T cells, Tregs) and myeloid cells (DCs, TAMs, MDSCs), where VEGF can have direct effects on immune cell phenotype and function. Thus, it is not surprising that strategies targeting VEGF/VEGFRs have shown efficacy in alleviating tumor-associated immunosuppression and have been combined with immunotherapies, especially immune checkpoint blockade. In this review, we discuss the direct and indirect effects of VEGF on the immunosuppressive tumor microenvironment with particular focus on the direct regulation of immune cells through VEGFR2 activity. We also summarize preclinical and clinical observations of combining antiangiogenesis agents with immunotherapies for the treatment of solid tumors.

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Section: Type I Ifn and Sting Agonistsmentioning

confidence: 99%

Section: Antiangiogenic Therapy In Combination With Immunotherapymentioning

confidence: 99%

Direct and indirect regulation of the tumor immune microenvironment by VEGF

Zhang

Brekken

2022

Journal of Leukocyte Biology

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“…Other convincing studies exploiting distinct immunocompetent mouse tumor models have provided further evidence for a causal role of AXL in mounting an immunosuppressive TIME ( 182 – 184 ). A recent study found that mice bearing KPL ( Stk11/Kras/Trp53 mutants) lung tumors are refractory to anti-PD-1 ( 184 ). Bemcentinib treatment resulted in significant re-sensitization to anti-PD-1, and correlated with increased TCF1-expressing CD8 T cells.…”

Section: Evidence For Axl-mediated Time Remodeling Immunosuppression ...mentioning

confidence: 99%

Dissecting the Role of AXL in Cancer Immune Escape and Resistance to Immune Checkpoint Inhibition

et al. 2022

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The development and implementation of Immune Checkpoint Inhibitors (ICI) in clinical oncology have significantly improved the survival of a subset of cancer patients with metastatic disease previously considered uniformly lethal. However, the low response rates and the low number of patients with durable clinical responses remain major concerns and underscore the limited understanding of mechanisms regulating anti-tumor immunity and tumor immune resistance. There is an urgent unmet need for novel approaches to enhance the efficacy of ICI in the clinic, and for predictive tools that can accurately predict ICI responders based on the composition of their tumor microenvironment. The receptor tyrosine kinase (RTK) AXL has been associated with poor prognosis in numerous malignancies and the emergence of therapy resistance. AXL is a member of the TYRO3-AXL-MERTK (TAM) kinase family. Upon binding to its ligand GAS6, AXL regulates cell signaling cascades and cellular communication between various components of the tumor microenvironment, including cancer cells, endothelial cells, and immune cells. Converging evidence points to AXL as an attractive molecular target to overcome therapy resistance and immunosuppression, supported by the potential of AXL inhibitors to improve ICI efficacy. Here, we review the current literature on the prominent role of AXL in regulating cancer progression, with particular attention to its effects on anti-tumor immune response and resistance to ICI. We discuss future directions with the aim to understand better the complex role of AXL and TAM receptors in cancer and the potential value of this knowledge and targeted inhibition for the benefit of cancer patients.

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“…This allows for evaluation of toxicities, including on-target/off-tumor side effects, and the immunosuppressive microenvironments [ 53 ]. Now, due to the growing worldwide enthusiasm in cancer immunotherapy, syngeneic murine models are widely used tools for studying tumor immunity and immunotherapy response because there is a fully functional murine immune system [ 51 , 54 , 55 ].…”

Section: Classification Of Animal Modelsmentioning

confidence: 99%

Research Status of Mouse Models for Non-Small-Cell Lung Cancer (NSCLC) and Antitumor Therapy of Traditional Chinese Medicine (TCM) in Mouse Models

Chen¹,

Zheng

Zhang

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Non-small-cell lung cancer (NSCLC) is known as one of the most lethal cancers, causing more than 1 million deaths annually worldwide. Therefore, the development of novel therapeutic drugs for NSCLC has become an urgent need. Herein, various mouse models provide great convenience not only for researchers but also for the development of antitumor drug. Meanwhile, TCM, as a valuable and largely untapped resource pool for modern medicine, provides research resources for the treatment of various diseases. Until now, cell-derived xenograft (CDX) model, patient-derived xenograft (PDX) model, syngeneic model, orthotopic model, humanized mouse model (HIS), and genetically engineered mouse models (GEMMs) have been reported in TCM evaluation. This review shows the role and current status of kinds of mouse models in antitumor research and summarizes the application progress of TCM including extracts, formulas, and isolated single molecules for NSCLC therapy in various mouse models; more importantly, it provides a theoretical exploration of what kind of mouse models is ideal for TCM efficacy evaluation in future. However, there are still huge challenges and limitations in the development of mouse models specifically for the TCM research, and none of the available models are perfectly matching the characteristics of TCM, which suppress the tumor growth through various mechanisms, especially by regulating immune function. Nevertheless, with fully functional immune system existing in syngeneic model and humanized mouse model (HIS), it is still suggested that these two models are more suitable for development of TCM especially for TCM extracts or formulas. Moreover, continued efforts are needed to generate more reliable mouse models to test TCM formulas in future research.

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AXL targeting restores PD-1 blockade sensitivity of STK11/LKB1 mutant NSCLC through expansion of TCF1+ CD8 T cells

Cited by 43 publications

References 68 publications

Direct and indirect regulation of the tumor immune microenvironment by VEGF

Direct and indirect regulation of the tumor immune microenvironment by VEGF

Dissecting the Role of AXL in Cancer Immune Escape and Resistance to Immune Checkpoint Inhibition

Research Status of Mouse Models for Non-Small-Cell Lung Cancer (NSCLC) and Antitumor Therapy of Traditional Chinese Medicine (TCM) in Mouse Models

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