Astragalus polysaccharide antagonized anti PD-1 efficacy in melanoma through inhibiting JAK-STAT1/CIITA and TLR/NF-κB signaling.
Advanced melanoma remains a major clinical challenge due to resistance to immune checkpoint inhibitors (ICIs, e.g., anti PD-1). Astragalus Polysaccharide (APS) is a clinically approved immunomodulator for cancer treatment. However, its interaction with anti PD-1 remains largely unknown. This study aims to explore the efficacy and underlying mechanism of APS combined with anti PD-1 in melanoma.
For in vivo studies, the anti-tumor effect of APS combined with anti PD-1 was evaluated in a B16-OVA melanoma mouse model. For mechanism exploration, immunohistochemistry, flow cytometry, ELISA, PCR array, qRT-PCR, Western blotting and confocal microscopy were employed to detect tumor immune microenvironment changes and related signaling pathway activation.
Unexpectedly, APS significantly antagonized the anti-tumor efficacy of anti PD-1 in melanoma mice. APS reversed anti PD-1-induced infiltration of CD4+ T cells, CD8+ T cells and dendritic cells (DCs) in the tumor microenvironment, and impaired DC maturation and CD4+ T cell activation. Mechanistically, APS significantly inhibited JAK-STAT1 signaling, downregulated MHCII master regulator CIITA, and subsequently reduced MHCII expression. Meanwhile, APS markedly suppressed TLR signaling and attenuated NF-κB mediated inflammatory responses in B16-OVA melanoma cells and DCs.
APS antagonized anti PD-1 efficacy by inducing an immunosuppressive microenvironment via dual inhibition of JAK-STAT1/CIITA signaling and TLR/NF-κB signaling. This study suggests that the combination of natural polysaccharides and ICIs may warrant caution, although further studies are needed to validate these findings and determine their clinical relevance.
For in vivo studies, the anti-tumor effect of APS combined with anti PD-1 was evaluated in a B16-OVA melanoma mouse model. For mechanism exploration, immunohistochemistry, flow cytometry, ELISA, PCR array, qRT-PCR, Western blotting and confocal microscopy were employed to detect tumor immune microenvironment changes and related signaling pathway activation.
Unexpectedly, APS significantly antagonized the anti-tumor efficacy of anti PD-1 in melanoma mice. APS reversed anti PD-1-induced infiltration of CD4+ T cells, CD8+ T cells and dendritic cells (DCs) in the tumor microenvironment, and impaired DC maturation and CD4+ T cell activation. Mechanistically, APS significantly inhibited JAK-STAT1 signaling, downregulated MHCII master regulator CIITA, and subsequently reduced MHCII expression. Meanwhile, APS markedly suppressed TLR signaling and attenuated NF-κB mediated inflammatory responses in B16-OVA melanoma cells and DCs.
APS antagonized anti PD-1 efficacy by inducing an immunosuppressive microenvironment via dual inhibition of JAK-STAT1/CIITA signaling and TLR/NF-κB signaling. This study suggests that the combination of natural polysaccharides and ICIs may warrant caution, although further studies are needed to validate these findings and determine their clinical relevance.
Authors
Wang Wang, Li Li, Liu Liu, Yu Yu, Peng Peng, Deng Deng, Lei Lei, Liu Liu, Li Li, Leong Leong, Ren Ren, Wu Wu
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