MerTK as a therapeutic target in glioblastoma

Wu, Jing; Frady, Lauren N.; Bash, Ryan; Cohen, Stephanie M.; Schorzman, Allison N.; Su, Yu Ting; Irvin, David M.; Zamboni, William C.; Wang, Xiaodong; Frye, Stephen V.; Ewend, Matthew G.; Sulman, Erik P.; Gilbert, Mark R.; Earp, H. Shelton; Miller, C. Ryan

doi:10.1093/neuonc/nox111

Cited by 67 publications

(66 citation statements)

References 42 publications

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“…TAM receptor family member mediated regulation of the T cell response within the tumor is an active area of clinical and pre-clinical research (Myers et al, 2019;Wu et al, 2018a). Mertk specific inhibition has been shown to suppress tumor growth in murine solid tumor models (Cook et al, 2013;Sinik et al, 2018;Wu et al, 2018b). Additionally, suppression of TAM receptor signaling has been shown to increase the response to anti-PD-1 therapy in a murine tumor model, suggesting that it is mediated by a mechanism other than PD-1 signaling (Kasikara et al, 2019), as we have observed in our autoimmune models.…”

Section: Mertk Regulates T Cell Arrest In a Solid Tumorsupporting

confidence: 73%

MERTK on mononuclear phagocytes regulates T cell antigen recognition at autoimmune and tumor sites

Lindsay

Dew²,

Rodrı́guez³

et al. 2019

Preprint

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Understanding mechanisms of immune regulation is key to developing effective immunotherapies for autoimmunity and cancer; however, many regulatory mechanisms have not been elucidated. By analyzing T cell motility and activation at the disease site as well as disease progression, we examined the role of mononuclear phagocytes in driving regulation of effector T cells in type 1 diabetes and melanoma. We report that mononuclear phagocytes in the islets impair T cell responsiveness to antigen by preventing antigen-mediated T cell arrest.Mononuclear phagocytes in the autoimmune lesion express the TAM family receptor tyrosine kinase Mertk which functions in efferocytosis. Inhibition or deficiency of Mertk led to a release from T cell regulation characterized by enhanced T cell arrest in pre-diabetic islets and at the tumor site. This T cell arrest was accompanied by increased T cell-antigen presenting cell interactions as well as increased antigen experience and effector function by T cells in the islets.Notably, the effect of Mertk inhibition on T cell regulation was only seen at the disease site in the islets, not in draining lymph nodes. Inhibition of Mertk-dependent T cell regulation culminated in the rapid acceleration of autoimmune pathology and disease. In human islets, the number of Mertk-expressing cells were increased in remaining insulin-containing islets from type 1 diabetic patients, suggesting that they might have a protective role in human disease. These data indicate that Mertk signaling in mononuclear phagocytes drives T cell regulation that functions specifically at the disease site in peripheral tissues through a mechanism that prevents T cell arrest and response to antigen.

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Section: Mertk Regulates T Cell Arrest In a Solid Tumorsupporting

confidence: 73%

MERTK on mononuclear phagocytes regulates T cell antigen recognition at autoimmune and tumor sites

Lindsay

Dew²,

Rodrı́guez³

et al. 2019

Preprint

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“…Its expression was shown to be higher in tumor recurrences. TAMs that express MerTK are also associated with tumor growth and resistance to treatment, making MerTK a potential therapeutic target (Wu et al, 2018). The molecular crosstalk between tumor cells and macrophages appears to be important for tumor growth and malignant progression.…”

Section: Tumor Cellsmentioning

confidence: 99%

Targeting Tumor Associated Macrophages to Overcome Conventional Treatment Resistance in Glioblastoma

et al. 2020

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“…This may play a role in the differential effects of treatment in Mertk −/− mice versus in vivo Mertk small molecule inhibition. Inhibition of Mertk with the small molecule inhibitor, UNC2025, did not affect tumor growth in murine orthotopic GBM tumor graft models [58], and combined treatment with UNC2025 and radiation therapy did not significantly increase overall survival compared with radiation alone. However, combined treatment did result in some tumor cures that were not seen in mice treated with radiation therapy alone [58].…”

mentioning

confidence: 91%

“…Inhibition of Mertk with the small molecule inhibitor, UNC2025, did not affect tumor growth in murine orthotopic GBM tumor graft models [58], and combined treatment with UNC2025 and radiation therapy did not significantly increase overall survival compared with radiation alone. However, combined treatment did result in some tumor cures that were not seen in mice treated with radiation therapy alone [58]. In contrast, Mertk −/− mice bearing CT26 colorectal carcinoma showed significantly increased overall survival following radiation compared with wild-type mice [42].…”

mentioning

confidence: 91%

“…The related agent UNC569 induced apoptosis in acute lymphocytic leukemia (ALL) cell lines Jurkat and 697, and reduced colony formation in ALL and pediatric atypical teratoid rhabdoid tumor cell lines compared with vehicle-treated and non-Mertk-targeted small molecule inhibitor controls [56]. Another related agent UNC2025 reduced cell proliferation and colony formation of U251, A172 and SF188 GBM cell lines in vitro [57], and in syngeneic orthotopic tumor studies was found to have significant penetration into tumors in the central nervous system resulting in delayed growth and increased response rate to radiation therapy [58]. UNC2025 inhibited Mertk phosphorylation in human nonsmall cell lung carcinoma (NSCLC) cell lines (H2228, A549, Colo699 and H1299), induced apoptosis and inhibited colony formation in vitro and inhibited growth of subcutaneous tumor xenografts with H2228 and A549 cells in Nude mice [59].…”

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confidence: 97%

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The TAM family as a therapeutic target in combination with radiation therapy

Tormoen

Crittenden

Gough

2017

Emerging Topics in Life Sciences

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Radiation therapy is primarily a modality to kill cancer cells in the treatment field. It is becoming increasingly clear that radiation therapy can also be used to direct immune responses that have the potential to clear residual local or distant disease outside the treatment field. We believe that cancer cell death is the critical link between these processes. Understanding the handling of dying cancer cells by immune cells in the tumor environment is crucial to facilitate immune responses following radiation therapy. We review the role of the TAM (Tyro3 Axl Mertk) group of receptor tyrosine kinases and their role following radiation-induced cancer cell death in the tumor environment.Cell-mediated immunity to tumors is thought to require cytotoxic effector CD8 T cells expanded from naive precursors that can traffic to the tumor and kill their targets. Cancer cells can accumulate an array of mutated proteins with the potential to act as neoantigen targets for effector T cells, but cancer cells lack the requisite costimulatory molecules to active naive T cells and naive T cells do not traffic efficiently outside of lymphoid organs. Thus, to initiate new immune responses from naive T cells, the dogma is that dendritic cells (DCs) must serve to transport antigen from peripheral sites to lymphoid organs and cross-present antigen to CD8 T cells. One of the critical populations of dendritic cells for tumor immunity is the CD8a + CD103 + Batf3 + subpopulation, as these are uniquely capable of cross-presenting tumor-associated antigen on MHC class I [1,2]. Batf3 + cross-presenting dendritic cells are critical for T-cell-mediated rejection of immunogenic tumors [2], are required for T-cell-mediated rejection of tumors treated with immunotherapy [3], and are also required for tumor control by the combination of immunotherapy and radiation therapy [4]. However, the CD103 + Batf3 + dendritic cell is one of the least common myeloid cells in tumors, representing a mere 1-3% of immune cells in the tumor environment [1,5]. Tumor-associated macrophages can be 10-20× more common, and the less phagocytic granulocyte and immature monocyte subtypes may be more common than that [1,5]. Multiple studies have shown that tumors with high levels of myeloid infiltration are associated with poor prognosis; however, often these studies are unable to distinguish the various myeloid populations within the tumor environment which may explain mixed results upon meta-analysis [6,7]. Thus, while targeted radiation leads to focused killing of cancer cells and release of cancer antigens and immune adjuvant within the irradiated tumor, the released antigen is most probably taken up by multiple myeloid populations other than CD103 + Batf3 + dendritic cells, and therefore, to cells incapable of initiating naive T-cell responses. If tumor immunity is to be facilitated with targeted radiation, then efficient delivery of irradiated cancer cell antigen to dendritic cells must be attained. For these reasons, it would be valuable to characterize individual c...

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MerTK as a therapeutic target in glioblastoma

Abstract: These results suggest that MerTK inhibition combined with XRT has a therapeutic effect in a subset of GBM. Further mechanistic studies are warranted.

Cited by 67 publications

References 42 publications

MERTK on mononuclear phagocytes regulates T cell antigen recognition at autoimmune and tumor sites

MERTK on mononuclear phagocytes regulates T cell antigen recognition at autoimmune and tumor sites

Targeting Tumor Associated Macrophages to Overcome Conventional Treatment Resistance in Glioblastoma

The TAM family as a therapeutic target in combination with radiation therapy

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