Colorectal cancer cell-derived CCL20 recruits regulatory T cells to promote chemoresistance via FOXO1/CEBPB/NF-κB signaling

Wang, Dan; Yang, Li; Yu, Wenbin; Wu, Qian; Lian, Jingyao; Li, Feng; Li, Shasha; Li, Aitian; He, Zhiang; Wang, Zhibin; Sun, Zhenqiang; Yuan, Weitang; Zhang, Yi

doi:10.1186/s40425-019-0701-2

Cited by 154 publications

(130 citation statements)

References 53 publications

(48 reference statements)

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“…6K, S7A). Studies of other cancers have demonstrated that CCL20 signaling can promote tumor growth, invasiveness and chemoresistance (Lee et al, 2017;Lu et al, 2017;Walch-Ruckheim et al, 2015) by recruitment of Tregs and/or T H 17 cells (Walch-Ruckheim et al, 2015;Wang et al, 2019). CCL20 expression on the protein level was confirmed with ELISA using plasma from different bone marrow fractions (Supplementary Table 6).…”

Section: Coordination Between Myeloid and Lymphoid Compartmentsmentioning

confidence: 79%

Human prostate cancer bone metastases have an actionable immunosuppressive microenvironment

Baryawno

Kfoury

Sévère

et al. 2020

Preprint

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Cancer-related mortality due to solid tumor malignancies is overwhelmingly due to the development and progression of metastases. In advanced prostate cancer, metastases most often involve the bone 1 and generally represent incurable disease. It remains unclear what aspects of the bone marrow microenvironment make it hospitable to metastatic dissemination. Similarly, the impact of the metastatic tumor on hematopoiesis and the marrow immune response is poorly understood. Here we take advantage of rare spinal cord decompression surgeries to profile marrow and metastatic tumors from men with advanced prostate cancer at single-cell resolution. We contrast the cellular composition and transcriptional states in matched samples of tumor and liquid bone marrow collected at adjacent vertebral body levels, as well as bone marrow of orthopedic patients without malignancy.Metastatic prostate cancer was associated with hematopoietic suppression and multifaceted immune distortion. There was exhaustion of specific T-cell subsets, appearance of inflammatory lymphocytes and macrophages, and alteration of cytokine profiles. The chemokine CCL20 was notably overexpressed by myeloid cells, as was its cognate CCR6 receptor on T-cells. This dual overexpression was associated with repressed immune responses. We used a syngeneic mouse model of bone-metastatic prostate cancer to explore this observation, and demonstrated that disruption of the CCL20-CCR6 axis resulted in significant prolongation of survival. Overall, comparative high-resolution analysis of bone marrow reveals distinct alterations associated with prostate cancer bone metastases that may be amenable to therapeutic targeting with the goal of altering cancer progression.3 ManuscriptProstate cancer frequently metastasizes to bone where, in the castration-resistant setting, 70 to 90% of patients have radiographically-detectable skeletal involvement 1-5 . To date, bone metastases represent a generally incurable form of prostate cancer and contribute significantly to disease-specific morbidity 6 . In particular, metastatic involvement of the spinal column can result in pathologic fracture and spinal cord compression leading to significant neurologic and functional disability. Surgical decompression/stabilization and targeted radiation are used selectively. Approved bone-targeted systemic therapies offer some benefit. Zoledronic acid and denosumab delay skeletal morbidity but do not improve overall survival 7 . The radiopharmaceutical radium-223 offers a modest improvement in overall survival 8 . The immune checkpoint therapies targeting CTLA4 and PD-1/PD-L1 have been unsuccessful in clinical trials in unselected prostate cancer populations 9 despite the high abundance of T lymphocytes in the tissue. In particular, emerging evidence indicates that patients with bone metastases are at a disadvantage when it comes to response to immune checkpoint therapies 10 .Altogether, this indicates that there is a clear need for new and more effective approaches for our patients with bone metast...

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Section: Coordination Between Myeloid and Lymphoid Compartmentsmentioning

confidence: 79%

Human prostate cancer bone metastases have an actionable immunosuppressive microenvironment

Baryawno

Kfoury

Sévère

et al. 2020

Preprint

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“…According to RECIST 1.1 criteria, CRC patients were divided into Sensitive-CRC group (containing Complete Response, Partial Response and Stable Disease) and Resistant-CRC group (Progressive Disease). 25 This research had granted approval by the Ethics Committee of The Sixth Affiliated Hospital of Sun Yat-sen University.…”

Section: Patients and Methods Patientsmentioning

confidence: 99%

<p>lncRNA UCA1 Contributes to 5-Fluorouracil Resistance of Colorectal Cancer Cells Through miR-23b-3p/ZNF281 Axis</p>

Xian¹,

Hu²,

Wang³

et al. 2020

OTT

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The chemoresistance of 5-fluorouracil (5-FU) limited the application of chemotherapy in colorectal cancer (CRC) treatment. Herein, we aimed to uncover the potential mechanism behind the 5-FU resistance of CRC cells. Methods: The abundance of long noncoding RNA urothelial carcinoma associated 1 (lncRNA UCA1), microRNA-23b-3p (miR-23b-3p) and zinc finger protein 281 (ZNF281) was measured by quantitative real-time polymerase chain reaction (qRT-PCR) in CRC tissues and cells. Western blot was conducted to examine autophagy-related proteins, apoptosisassociated proteins and ZNF281 in CRC tissues and cells. Cell counting kit-8 (CCK8) assay was performed to detect the viability and inhibitory concentration 50% (IC50) value of 5-FU of CRC cells. The apoptosis of CRC cells was measured by flow cytometry. The binding sites between miR-23b-3p and UCA1 or ZNF281 were predicted by miRcode and Starbase software, respectively, and the combination was confirmed by dual-luciferase reporter assay and RIP assay. Murine xenograft model was established to verify the role of UCA1 on the 5-FU resistance of CRC in vivo. Results: The 5-FU resistance of CRC was positively related to the level of UCA1 and autophagy. UCA1 accelerated the 5-FU resistance of CRC cells through facilitating autophagy and suppressing apoptosis. MiR-23b-3p was a target of UCA1 in 293T and CRC cells. The knockdown of miR-23b-3p reversed the inhibitory effects of UCA1 interference on the 5-FU resistance and autophagy and the promoting impact on the apoptosis of CRC cells. ZNF281 could bind to miR-23b-3p in 293T cells. MiR-23b-3p elevated the 5-FU sensitivity through down-regulating ZNF281 in CRC cells. UCA1 interference enhanced the 5-FU sensitivity of CRC through miR-23b-3p/ZNF281 axis in vivo. Conclusion: UCA1 mediated 5-FU resistance of CRC cells through facilitating autophagy and inhibiting apoptosis via miR-23b-3p/ZNF281 axis in vivo and in vitro.

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“…For example, cells that die from chemotherapy release molecules that regulate the immune response, stimulate angiogenesis, alter the physicochemical parameters of the tumor microenvironment, or activate cellular invasion [216]. An immunosuppressive effect has been shown for molecules released by dying cancer cells, e.g., secreted CCL20 recruits regulatory T cells via the FOXO1/CEBPB/NF-κB signaling [217]; sphingosine-1 phosphate activates and polarizes of tumor-associated macrophages into M2 macrophages. These M2 macrophages secrete anti-inflammatory IL-10, and PGE2 supporting the migration of endothelial cells and angiogenesis [218].…”

Section: Communication Between Cancer Cells and Surrounding Stromal Cmentioning

confidence: 99%

New Insights into Therapy-Induced Progression of Cancer

Shnaider

Ivanova

Malyants

et al. 2020

IJMS

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The malignant tumor is a complex heterogeneous set of cells functioning in a no less heterogeneous microenvironment. Like any dynamic system, cancerous tumors evolve and undergo changes in response to external influences, including therapy. Initially, most tumors are susceptible to treatment. However, remaining cancer cells may rapidly reestablish the tumor after a temporary remission. These new populations of malignant cells usually have increased resistance not only to the first-line agent, but also to the second- and third-line drugs, leading to a significant decrease in patient survival. Multiple studies describe the mechanism of acquired therapy resistance. In past decades, it became clear that, in addition to the simple selection of pre-existing resistant clones, therapy induces a highly complicated and tightly regulated molecular response that allows tumors to adapt to current and even subsequent therapeutic interventions. This review summarizes mechanisms of acquired resistance, such as secondary genetic alterations, impaired function of drug transporters, and autophagy. Moreover, we describe less obvious molecular aspects of therapy resistance in cancers, including epithelial-to-mesenchymal transition, cell cycle alterations, and the role of intercellular communication. Understanding these molecular mechanisms will be beneficial in finding novel therapeutic approaches for cancer therapy.

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Colorectal cancer cell-derived CCL20 recruits regulatory T cells to promote chemoresistance via FOXO1/CEBPB/NF-κB signaling

Cited by 154 publications

References 53 publications

Human prostate cancer bone metastases have an actionable immunosuppressive microenvironment

Human prostate cancer bone metastases have an actionable immunosuppressive microenvironment

<p>lncRNA UCA1 Contributes to 5-Fluorouracil Resistance of Colorectal Cancer Cells Through miR-23b-3p/ZNF281 Axis</p>

New Insights into Therapy-Induced Progression of Cancer

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