Author
Listed:
- Xiaocheng Wang
(Sun Yat-sen University)
- Maosheng Cheng
(Sun Yat-sen University)
- Shuang Chen
(Sun Yat-sen University)
- Caihua Zhang
(Sun Yat-sen University)
- Rongsong Ling
(Sun Yat-sen University)
- Shuqing Qiu
(Sun Yat-sen University)
- Ke Chen
(Sun Yat-sen University)
- Bin Zhou
(University of Chinese Academy of Sciences)
- Qiuli Li
(Sun Yat-sen University Cancer Center)
- Wenbin Lei
(Sun Yat-sen University)
- Demeng Chen
(Sun Yat-sen University
Sun Yat-sen University Cancer Center)
Abstract
Relatlimab and nivolumab combination therapy shows significant efficacy in treating various types of cancer. Current research on the molecular mechanisms of this treatment is abundant, but in-depth investigations into post-treatment resistance remain notably lacking. In this study, we identify significant enrichment of SRY (sex determining region Y)-box 9 (Sox9)+ tumor cells in resistant samples using single cell RNA sequencing (scRNAseq) in a head and neck squamous cell carcinoma (HNSCC) mouse model. In addition, Sox9 directly regulates the expression of annexin A1 (Anxa1), mediating apoptosis of formyl peptide receptor 1 (Fpr1)+ neutrophils through the Anxa1-Fpr1 axis, which promotes mitochondrial fission, inhibits mitophagy by downregulating BCL2/adenovirus E1B interacting protein 3 (Bnip3) expression and ultimately prevents the accumulation of neutrophils in tumor tissues. The reduction of Fpr1+ neutrophils impairs the infiltration and tumor cell-killing ability of cytotoxic Cd8 T and γδT cells within the tumor microenvironment, thereby leading to the development of resistance to the combination therapy. We further validate these findings using various transgenic mouse models. Overall, this study comprehensively explains the mechanisms underlying resistance to the anti-LAG-3 plus anti-PD-1 combination therapy and identifies potential therapeutic targets to overcome this resistance.
Suggested Citation
Xiaocheng Wang & Maosheng Cheng & Shuang Chen & Caihua Zhang & Rongsong Ling & Shuqing Qiu & Ke Chen & Bin Zhou & Qiuli Li & Wenbin Lei & Demeng Chen, 2025.
"Resistance to anti-LAG-3 plus anti-PD-1 therapy in head and neck cancer is mediated by Sox9+ tumor cells interaction with Fpr1+ neutrophils,"
Nature Communications, Nature, vol. 16(1), pages 1-20, December.
Handle:
RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59050-4
DOI: 10.1038/s41467-025-59050-4
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