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
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 ident...
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Nature Portfolio
2025-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59050-4 |
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| author | Xiaochen Wang Maosheng Cheng Shuang Chen Caihua Zhang Rongsong Ling Shuqing Qiu Ke Chen Bin Zhou Qiuli Li Wenbin Lei Demeng Chen |
| author_facet | Xiaochen Wang Maosheng Cheng Shuang Chen Caihua Zhang Rongsong Ling Shuqing Qiu Ke Chen Bin Zhou Qiuli Li Wenbin Lei Demeng Chen |
| author_sort | Xiaochen Wang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-e64388235d5441279e6f1cd033812151 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-e64388235d5441279e6f1cd0338121512025-08-20T03:16:47ZengNature PortfolioNature Communications2041-17232025-04-0116112010.1038/s41467-025-59050-4Resistance to anti-LAG-3 plus anti-PD-1 therapy in head and neck cancer is mediated by Sox9+ tumor cells interaction with Fpr1+ neutrophilsXiaochen Wang0Maosheng Cheng1Shuang Chen2Caihua Zhang3Rongsong Ling4Shuqing Qiu5Ke Chen6Bin Zhou7Qiuli Li8Wenbin Lei9Demeng Chen10Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen UniversityOtorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen UniversityOtorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen UniversityOtorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen UniversityOtorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen UniversityOtorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen UniversityOtorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen UniversityState Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of SciencesDepartment of Head and Neck Surgery, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterOtorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen UniversityOtorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen UniversityAbstract 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.https://doi.org/10.1038/s41467-025-59050-4 |
| spellingShingle | Xiaochen Wang Maosheng Cheng Shuang Chen Caihua Zhang Rongsong Ling Shuqing Qiu Ke Chen Bin Zhou Qiuli Li Wenbin Lei Demeng Chen 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 |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| url | https://doi.org/10.1038/s41467-025-59050-4 |
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