CXCL8 induces M2 macrophage polarization and inhibits CD8+ T cell infiltration to generate an immunosuppressive microenvironment in colorectal cancer

Abstract

The poor prognosis of immunotherapy in patients with colorectal cancer (CRC) necessitates a comprehensive understanding of the immunosuppressive mechanisms within tumor microenvironment (TME). Undoubtedly, the anti-tumor immune cells play an indispensable role in immune tolerance. Therefore, it is imperative to investigate novel immune-related factors that have the capacity to enhance anti-tumor immunity. Here, we employed bioinformatic analysis using R and Cytoscape to identify the hub gene chemokine (C-X-C motif) ligand 8 (CXCL8), which is overexpressed in CRC, in the malignant progression of CRC. However, its specific role of CXCL8 in CRC immunity remains to be elucidated. For this purpose, we evaluated how tumor-derived CXCL8 promotes M2 macrophage infiltration by in vivo and in vitro, which can be triggered by IL-1β within TME. Mechanistically, CXCL8-induced polarization of M2 macrophages depends on the activation of the STAT3 signaling. Finally, immunohistochemistry and multiplexed immunohistochemistry analysis identified that CXCL8 not only enhances PD-L1⁺ M2 macrophage infiltration but also attenuates the recruitment of PD-1⁺ CD8⁺ T cells in murine CRC models. Together, these findings emphasize the critical role for CXCL8 in promoting M2 macrophage polarization and inhibiting CD8⁺ T cell infiltration, thereby links CXCL8 to the emergency of immunosuppressive microenvironment facilitating tumor evasion. Overall, these findings may provide novel strategy for CRC immunotherapy.

Keywords: CD8 T cell; CXCL8; M2 macrophage; colorectal cancer; immunosuppression.