Rab37 in lung cancer mediates exocytosis of soluble ST2 and thus skews macrophages toward tumor‐suppressing phenotype

Tzeng, Hong Tai; Su, Ching Chin; Chang, Chih Peng; Lai, Wu‐Wei; Su, Wu Chou; Wang, Yi‐Ching

doi:10.1002/ijc.31569

Cited by 27 publications

(23 citation statements)

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“…Meanwhile, GBP5 expression in CM is associated with favorable prognosis (Wang et al, 2018). RAB37 , as a tumor suppressor gene, promotes M1-like macrophage infiltration and suppresses tumor growth (Tzeng et al, 2018), and it was frequently down-regulated due to promoter hypermethylation in metastatic lung cancer, can serve as a potential predictive biomarker (Wu et al, 2009). RAB37 -mediated SFRP1 secretion suppresses cancer stemness, and dysregulated RAB37-SFRP1 pathway confers cancer stemness via the activation of Wnt signaling (Cho et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

A four-DNA methylation biomarker is a superior predictor of survival of patients with cutaneous melanoma

Guo

Zhu

et al. 2019

eLife

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Cutaneous melanoma (CM) is a life-threatening form of skin cancer. Prognostic biomarkers can reliably stratify patients at initial melanoma diagnosis according to risk, and may inform clinical decisions. Here, we performed a retrospective, cohort-based study analyzing genome-wide DNA methylation of 461 patients with CM from the TCGA database. Cox regression analyses were conducted to establish a four-DNA methylation signature that was significantly associated with the overall survival (OS) of patients with CM, and that was validated in an independent cohort. Corresponding Kaplan–Meier analysis displayed a distinct separation in OS. The ROC analysis confirmed that the predictive signature performed well. Notably, this signature exhibited much higher predictive accuracy in comparison with known biomarkers. This signature was significantly correlated with immune checkpoint blockade (ICB) immunotherapy-related signatures, and may have potential as a guide for measures of responsiveness to ICB immunotherapy.

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Section: Discussionmentioning

confidence: 99%

A four-DNA methylation biomarker is a superior predictor of survival of patients with cutaneous melanoma

Guo

Zhu

et al. 2019

eLife

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“…There is a positive feedback loop of interaction between CSCs with M2 cells in which CSCs secrete TGF-β to stimulate M2 cells for secreting IL-37 that, in turn, potentiates self-renewal, pluripotency, and invasive features of CSCs, as shown in pancreatic cancer (Sainz et al, 2015). and induce M2 polarization (Tzeng et al, 2018). In addition, IL-6 release from CSCs is important not only for sustaining their stemness (self-renewal) but also for activating Tregs, inactivating CTLs and inducing macrophage polarity toward a protumor M2-like phenotype (L. Kato et al, 2018;Lytle et al, 2018;Su et al, 2018).…”

Section: Endothelial Cellsmentioning

confidence: 99%

Cancer stem cells (CSCs) in cancer progression and therapy

Najafi

Farhood

Mortezaee

2018

Journal Cellular Physiology

429

268

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Cancer stem cells (CSCs) are self‐renewable cell types that are identified in most types of liquid and solid cancers and contributed to tumor onset, expansion, resistance, recurrence, and metastasis after therapy. CSCs are identified from the expression of cell surface markers, which is tumor‐type dependent. The transition between CSCs with cancer cells and other non‐CSCs occurs in cancers, which is possibly under the control of signals from CSCs and tumor microenvironment (TME), including CSC niche. Cancer‐associated fibroblasts are among the most influential cells for promoting both differentiation of CSCs and dedifferentiation of non‐CSCs toward attaining a CSC‐like phenotype. WNT/β‐catenin, transforming growth factor‐β, Hedgehog, and Notch are important signals for maintaining self‐renewal in CSCs. An effective therapeutic strategy relies on targeting both CSCs and non‐CSCs to remove a possible chance of tumor relapse. There are multiple ways to target CSCs, including immunotherapy, hormone therapy, (mi)siRNA delivery, and gene knockout. Such approaches can be designed for suppressing CSC stemness, tumorigenic cues from TME, CSC extrinsic and/or intrinsic signaling, hypoxia or for promoting differentiation in the cells. Because of sharing a range of characteristics to normal stem/progenitor cells, CSCs must be targeted based on their unique markers and their preferential expression of antigens.

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“…We have previously reported that Rab37 mediates exocytosis of several secretion factors in non-small cell lung (NSCLC) cells 18 , 19 . In addition, Rab37 facilitates soluble IL-1 receptor-like protein secretion in NSCLC cells to antagonize IL-33-mediated M2 macrophage polarization in TME 20 . To date, the role of Rab37 in tumor-infiltrating immune cells remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Converged Rab37/IL-6 trafficking and STAT3/PD-1 transcription axes elicit an immunosuppressive lung tumor microenvironment

Kuo

Yang

et al. 2021

Theranostics

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Background: Increased IL-6 level, M2 macrophages and PD-1 + CD8 + T cells in tumor microenvironments (TME) have been identified to correlate with resistance to checkpoint blockade immunotherapy, yet the mechanism remains poorly understood. Rab small GTPase-mediated trafficking of cytokines is critical in immuno-modulation. We have previously reported dysregulation of Rab37 in lung cancer cells, whereas the roles of Rab37 in tumor-infiltrating immune cells and cancer immunotherapy are unclear. Methods: The tumor growth of the syngeneic mouse allograft in wild type or Rab37 knockout mice was analyzed. Imaging analyses and vesicle isolation were conducted to determine Rab37-mediated IL-6 secretion. STAT3 binding sites at PD-1 promoter in T cells were identified by chromatin immunoprecipitation assay. Multiplex fluorescence immunohistochemistry was performed to detect the protein level of Rab37, IL-6 and PD-1 and localization of the tumor-infiltrating immune cells in allografts from mice or tumor specimens from lung cancer patients. Results: We revealed that Rab37 regulates the secretion of IL-6 in a GTPase-dependent manner in macrophages to trigger M2 polarization. Macrophage-derived IL-6 promotes STAT3-dependent PD-1 mRNA expression in CD8 + T cells. Clinically, tumors with high stromal Rab37 and IL-6 expression coincide with tumor infiltrating M2-macrophages and PD1 + CD8 + T cells that predicts poor prognosis in lung cancer patients. In addition, lung cancer patients with an increase in plasma IL-6 level are found to be associated with immunotherapeutic resistance. Importantly, combined blockade of IL-6 and CTLA-4 improves survival of tumor-bearing mice by reducing infiltration of PD1 + CD8 + T cells and M2 macrophages in TME. Conclusions: Rab37/IL-6 trafficking pathway links with IL-6/STAT3/PD-1 transcription regulation to foster an immunosuppressive TME and combined IL-6/CTLA-4 blockade therapy exerts potent anti-tumor efficacy.

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Rab37 in lung cancer mediates exocytosis of soluble ST2 and thus skews macrophages toward tumor‐suppressing phenotype

Cited by 27 publications

References 50 publications

A four-DNA methylation biomarker is a superior predictor of survival of patients with cutaneous melanoma

A four-DNA methylation biomarker is a superior predictor of survival of patients with cutaneous melanoma

Cancer stem cells (CSCs) in cancer progression and therapy

Converged Rab37/IL-6 trafficking and STAT3/PD-1 transcription axes elicit an immunosuppressive lung tumor microenvironment

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