Discover oncology · 2026
Circ_0001313 promotes an immunosuppressive tumor microenvironment through GM-CSF-associated granulocytic myeloid cell activation in colorectal cancer.
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Liu Ya, Liu Longfei, Quan Yingping, Wang Li, Xing Jiaotao, Zhao Jun, Wang Hui
Аннотация
BACKGROUND: Circ_0001313 is upregulated in colorectal cancer (CRC) and has been implicated in tumor progression, but its role in remodeling the immune microenvironment remains incompletely defined. This study investigated whether circ_0001313 contributes to CRC progression in association with granulocytic myeloid-derived suppressor cell (gMDSC)-like immunosuppression.
METHODS: Circ_0001313 expression was evaluated by qRT-PCR in CRC tissues and cell lines. Functional studies were performed using transient siRNA-mediated circ_0001313 knockdown in MC38 cells, a syngeneic murine CRC model suitable for immunocompetent C57BL/6J mice, followed by subcutaneous tumor growth and experimental lung metastasis assays. Tumor immune composition was analyzed by flow cytometry, Ly6G+ granulocytic myeloid cell-mediated suppression of CD8 + T-cell proliferation was assessed by coculture, and tumor explant supernatant (TES) assays, qPCR, ELISA, and GM-CSF neutralization were used to examine a GM-CSF-associated mechanism linked to gMDSC-like activation.
RESULTS: Circ_0001313 was upregulated in CRC tissues and cell lines. Transient circ_0001313 knockdown suppressed primary tumor growth and prolonged survival in the lung metastasis model. Immune profiling showed increased intratumoral CD4 + and CD8 + T cells but reduced Ly6G+ granulocytic myeloid cell abundance after circ_0001313 silencing. Ly6G+ cells from circ_0001313-silenced tumors exhibited lower PD-L1 and arginase 1 expression and diminished suppression of CD8 + T-cell proliferation. Mechanistically, circ_0001313 depletion was associated with reduced tumor-derived GM-CSF expression, and GM-CSF neutralization attenuated TES-induced gMDSC-like activation.
CONCLUSION: Circ_0001313 promotes CRC progression, at least in part, by remodeling the tumor immune microenvironment through a GM-CSF-associated granulocytic suppressor program, supporting further evaluation of this axis as a potential therapeutic target in CRC.
METHODS: Circ_0001313 expression was evaluated by qRT-PCR in CRC tissues and cell lines. Functional studies were performed using transient siRNA-mediated circ_0001313 knockdown in MC38 cells, a syngeneic murine CRC model suitable for immunocompetent C57BL/6J mice, followed by subcutaneous tumor growth and experimental lung metastasis assays. Tumor immune composition was analyzed by flow cytometry, Ly6G+ granulocytic myeloid cell-mediated suppression of CD8 + T-cell proliferation was assessed by coculture, and tumor explant supernatant (TES) assays, qPCR, ELISA, and GM-CSF neutralization were used to examine a GM-CSF-associated mechanism linked to gMDSC-like activation.
RESULTS: Circ_0001313 was upregulated in CRC tissues and cell lines. Transient circ_0001313 knockdown suppressed primary tumor growth and prolonged survival in the lung metastasis model. Immune profiling showed increased intratumoral CD4 + and CD8 + T cells but reduced Ly6G+ granulocytic myeloid cell abundance after circ_0001313 silencing. Ly6G+ cells from circ_0001313-silenced tumors exhibited lower PD-L1 and arginase 1 expression and diminished suppression of CD8 + T-cell proliferation. Mechanistically, circ_0001313 depletion was associated with reduced tumor-derived GM-CSF expression, and GM-CSF neutralization attenuated TES-induced gMDSC-like activation.
CONCLUSION: Circ_0001313 promotes CRC progression, at least in part, by remodeling the tumor immune microenvironment through a GM-CSF-associated granulocytic suppressor program, supporting further evaluation of this axis as a potential therapeutic target in CRC.