Exosomal circ-CTNNB1 derived from colorectal cancer cells induces N2 polarization of neutrophils to promote colorectal cancer cell growth and immune escape

Neutrophils have been reported to promote tumorigenesis, tumor development, and immune escape. CircCTNNB1 has been identified as a novel tumor promoter and to be associated with the unfavorable prognosis of cancer patients. This study focused on exploring the role of circ-CTNNB1 in colorectal cancer (CRC) cell growth and its regulatory mechanism contributing to the intercellular communication between neutrophils and CRC cells. At first, circ-CTNNB1 was found to be highly expressed in CRC cells Functional assays were performed and the results indicated that silencing of circ-CTNNB1 suppressed CRC cell proliferation, accelerated cell apoptosis. After neutrophils were co-cultured with exosomes derived from CRC cells or circ-CTNNB1-silenced CRC cells, it was observed that CRC cells-derived exosomes suppressed the apoptosis of neutrophils but facilitated N2 polarization, whereas circ-CTNNB1-silenced CRC cells-derived exosomes had no significant effects on the functions of neutrophils. Mechanistic assays were conducted to explore the molecular relationships underlying circ-CTNNB1-induced CRC cell growth and immune escape. Noteworthily, circ-CTNNB1 sequestered miR3619-5p to up-regulate IKBKB, the key factor of NF-?B signaling pathway. Moreover, circ-CTNNB1 activated NF?B signaling pathway to increase PD-L1 expression and further stimulated N2 polarization of neutrophils, which contributed to the proliferation and immune escape of CRC cells. In summary, exosomal circ-CTNNB1 transmitted by CRC cells mediates N2 polarization of neutrophils to further promote CRC cell growth and immune escape.