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Published on: November 28, 2019
Macrophage PABPC4-SPP1 Axis Orchestrates Immunosuppression in Colorectal Cancer
Meng Wang1,2,3, Fang Yang1,4, Yuan Gao1,3
1Department of Pathophysiology, College of High Altitude Military Medicine, Third Military Medical University (Army Medical University), Chongqing, China.
Abstract:
Poly(A)-binding proteins (PABPs) are frequently dysregulated in cancers, yet their functional roles remain largely elusive. Here, we identify that PABPC4, a member of PABPs, is upregulated during colorectal cancer (CRC) progression and associated with poor prognosis. Single-cell transcriptomics reveals that PABPC4 is predominantly expressed in the macrophages of the tumor microenvironment (TME). Conditional knockout of Pabpc4 in macrophages (C4cKO) profoundly inhibited the progression of multiple cancers, including CRC, melanoma, and ovarian cancer. Mechanistically, C4cKO obviously enhances the local and systemic antitumor immunity, characterized by increased M1-like macrophages and cytotoxic CD8+ T cells, and reduced M2-like macrophages and myeloid-derived suppressor cells. Clearance of macrophages or CD8+ T cells could abolish C4cKO-stimulated antitumor immunity. We further demonstrate that PABPC4 stabilizes SPP1 mRNA via direct 3'UTR binding, and SPP1 restoration substantially reversed the enhanced antitumor immunity and tumor suppression in C4cKO mice. Clinically, elevated macrophage PABPC4-SPP1 axis activity in human CRC tissues correlates with immunosuppressive phenotypes, potential immunotherapy resistance, and poor survival of patients. Collectively, our results reveal a previously undiscovered PABPC4-SPP1 axis in macrophages, which induces tumor-promoting macrophages and CD8+ T cell dysfunction, thereby facilitating tumor progression. Targeting the PABPC4-SPP1 axis represents a promising strategy for cancer therapy.
Insights
Poly(A)-binding protein C4 (PABPC4) promotes cancer by suppressing antitumor immunity in macrophages. Inhibiting the PABPC4-SPP1 axis enhances immune responses and tumor suppression, offering a new cancer therapy strategy.
Area of Science:
- Immunology
- Molecular Biology
- Oncology
Background:
- Poly(A)-binding proteins (PABPs) are implicated in cancer, but their specific roles are unclear.
- PABPC4 dysregulation is observed in various cancers, correlating with poor patient prognosis.
Purpose of the Study:
- To investigate the role of PABPC4 in colorectal cancer (CRC) progression and the tumor microenvironment (TME).
- To elucidate the molecular mechanisms by which PABPC4 influences antitumor immunity.
- To evaluate the therapeutic potential of targeting the PABPC4-SPP1 axis.
Main Methods:
- Single-cell transcriptomics to identify PABPC4 expression in the TME.
- Conditional knockout of Pabpc4 in macrophages (C4cKO) in mouse cancer models.
- Analysis of immune cell populations (M1/M2 macrophages, CD8+ T cells, MDSCs) in C4cKO mice.
- mRNA stabilization assays and SPP1 restoration experiments.
- Clinical correlation analysis of PABPC4-SPP1 axis activity in human CRC tissues.
Main Results:
- PABPC4 is upregulated in CRC and predominantly expressed in tumor-associated macrophages.
- Macrophage-specific knockout of PABPC4 (C4cKO) significantly inhibited CRC, melanoma, and ovarian cancer progression.
- C4cKO enhanced antitumor immunity by increasing M1 macrophages and CD8+ T cells while decreasing M2 macrophages and MDSCs.
- PABPC4 stabilizes SPP1 mRNA, and SPP1 restoration reversed the antitumor effects of C4cKO.
- Elevated macrophage PABPC4-SPP1 axis activity in human CRC correlates with immunosuppression and poor survival.
Conclusions:
- The PABPC4-SPP1 axis in macrophages promotes tumor progression by inducing immunosuppressive phenotypes and impairing CD8+ T cell function.
- Targeting the PABPC4-SPP1 axis is a promising therapeutic strategy for enhancing antitumor immunity and treating cancer.
