Modulating the Tumor Microenvironment via Oncolytic Viruses and CSF-1R Inhibition Synergistically Enhances Anti-PD-1 Immunotherapy

Shi, Gang; Yang, Qianmei; Zhang, Yujing; Jiang, Qingyuan; Lin, Yi; Yang, Shenshen; Wang, Huiling; Cheng, Lin; Zhang, Xin; Li, Yimin; Wang, Qingnan; Liu, Yi; Wang, Qin; Zhang, Hantao; Su, Xiaolan; Dai, Lei; Liu, Lei; Zhang, Shuang; Li, Jia; Li, Zhi; Yang, Yang; Yu, Dechao; Wei, Yuquan; Deng, Hongxin

doi:10.1016/j.ymthe.2018.11.010

Cited by 82 publications

(63 citation statements)

References 63 publications

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“…Pexidartinib (TURALIO™) is a novel, orally available small molecule tyrosine kinase inhibitor (TKI) with potent and selective activity against the colony-stimulating factor 1 (CSF1) receptor [1][2][3]. CSF1, expressed in high levels in several types of solid tumors, facilitates the differentiation of monocytes into tumor-associated macrophages (TAMs) and the survival of TAMs within the tumor microenvironment [4][5][6]. TAMs in turn have immunosuppressive effects and promote tumor growth and metastases [4,6].…”

Section: Introductionmentioning

confidence: 99%

“…CSF1, expressed in high levels in several types of solid tumors, facilitates the differentiation of monocytes into tumor-associated macrophages (TAMs) and the survival of TAMs within the tumor microenvironment [4][5][6]. TAMs in turn have immunosuppressive effects and promote tumor growth and metastases [4,6]. Pexidartinib also inhibits KIT proto-oncogene receptor tyrosine kinase (KIT) and FMS-like tyrosine kinase 3 harboring an internal tandem duplication mutation (FLT3-ITD) [2,3,7,8].…”

Section: Introductionmentioning

confidence: 99%

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Pexidartinib: First Approval

Lamb

2019

Drugs

156

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Pexidartinib (TURALIO™) is an orally administered small molecule tyrosine kinase inhibitor with selective activity against the colony-stimulating factor 1 (CSF1) receptor, KIT proto-oncogene receptor tyrosine kinase (KIT) and FMS-like tyrosine kinase 3 harboring an internal tandem duplication mutation (FLT3-ITD). In August 2019, the US FDA approved pexidartinib capsules for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery. This approval was based on positive results from the phase III ENLIVEN trial. Pexidartinib is being investigated in various malignancies as monotherapy or combination therapy. This article summarizes the milestones in the development of pexidartinib leading to its first approval for TGCT.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pexidartinib: First Approval

Lamb

2019

Drugs

156

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“…However, for the patients with Exhausted Immune Class tumors, due to in the tumor microenvironment comprising M2 macrophages, which promote tumor growth, and immunosuppressive factors like TGF-β, the combination of TGF-β and CSF1R inhibitors plus monoclonal antibody agents would be a good therapeutic option. 30,31 For remaining patients, we aim to recruit more immune-related components into the tumor microenvironment combined with immune checkpoint inhibitors against tumor progression, such as MALT1 inhibition by mepazine plus anti-PD-1. 32 In conclusion, our work identifies the novel immunophenotypes in LUAD based on the tumor microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Identification immunophenotyping of lung adenocarcinomas based on the tumor microenvironment

Tan

Huang

Deng

et al. 2020

J of Cellular Biochemistry

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The tumor immune microenvironment is heterogeneous, and its impact on treatment responses is not well understood. It is still a challenge to analyze the interaction between malignant cells and the tumor microenvironment to apply suitable immunotherapy in lung adenocarcinoma. We performed the nonnegative matrix factorization method to 513 messenger RNA expression profiles of lung adenocarcinomas (LUADs) from The Cancer Genome Atlas (TCGA) to obtain an immune‐related expression pattern. Subsequently, we characterized the immune‐related gene signatures and clinical and survival characteristics. We used 576 patients from Gene Expression Omnibus to confirm our findings. Of the patients in the training cohort, 51% had a high immune enrichment score, high expression of immune cell signaling, cytolytic activity, and interferon (IFN)‐related signatures (all P < .05). We denoted these as the Immune Class. We further subdivided the Immune Class into two subclasses based on the tumor microenvironment. These were denoted the Active Immune Class and Exhausted Immune Class. The former showed significant IFN, T‐cells, M1 macrophage signatures, and better prognosis (all P < .05), while the latter presented an exhausted immune response with activated stromal enrichment, M2 macrophage signatures, and immunosuppressive factors such as WNT/transforming growth factor‐β (all P < .05). Furthermore, we predicted the response of our immunophenotypes to immunological checkpoint inhibitors (P < .05). Our findings provide a novel insight into the immune‐related state of LUAD and can identify the patients who will be receptive to suitable immunotherapeutic treatments.

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“…CSF-1 and its receptor, colony-stimulating factor 1 receptor (CSF-1R), are areas of concern and are being developed in clinical research [47]. One feature that is encouraging here is identi cation of safe applications of immunotherapeutic or standard treatment tools [48][49][50]. Such promising activity has been demonstrated in autocrine CSF-1-based benign diffuse-type tenosynovial giant cell tumors [51,52].…”

Section: Discussionmentioning

confidence: 99%

SETDB1 promotes glioblastoma growth via CSF-1 - dependent macrophage recruitment by activating the AKT/mTOR signaling pathway

Han

Wei

Guo

et al. 2020

Preprint

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Background: Glioblastoma is a common disease of the central nervous system (CNS), with high morbidity and mortality. In the infiltrate in the tumor microenvironment, tumor-associated macrophages (TAMs) are abundant, which are important factors in glioblastoma progression. However, the exact details of TAMs in glioblastoma progression have yet to be determined. Methods: The clinical relevance of SET domain bifurcated 1 (SETDB1) was analyzed by immunohistochemistry, real-time PCR and Western blotting of glioblastoma tissues. SETDB1-induced cell proliferation, migration and invasion were investigated by CCK-8 assay, colony formation assay, wound healing and Transwell assay. The relationship between SETDB1 and colony stimulating factor 1 (CSF-1), as well as TAMs recruitment was examined by Western blotting, real-time PCR and syngeneic mouse model.Results: Our findings showed that SETDB1 upregulated in glioblastoma and relative to poor progression. Gain and loss of function approaches showed the SETDB1 overexpression promotes cell proliferation, migration and invasion in glioblastoma cells. However, knockdown SETDB1 exerted opposite effects in vitro. Moreover, SETDB1 promotes AKT/mTOR-dependent CSF-1 induction and secretion, which leads to macrophage recruitment in the tumor, resulted in tumor growth. Conclusion: Our research clarified that SETDB1 regulates of tumor microenvironment and hence presents a potential therapeutic target for treating glioblastoma.

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Modulating the Tumor Microenvironment via Oncolytic Viruses and CSF-1R Inhibition Synergistically Enhances Anti-PD-1 Immunotherapy

Cited by 82 publications

References 63 publications

Pexidartinib: First Approval

Pexidartinib: First Approval

Identification immunophenotyping of lung adenocarcinomas based on the tumor microenvironment

SETDB1 promotes glioblastoma growth via CSF-1 - dependent macrophage recruitment by activating the AKT/mTOR signaling pathway

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