Bladder cancer intrinsic LRFN2 drives anticancer immunotherapy resistance by attenuating CD8+ T cell infiltration and functional transition
Background Immune checkpoint inhibitor (ICI) therapy improves the survival of patients with advanced bladder cancer (BLCA); however, its overall effectiveness is limited, and many patients still develop immunotherapy resistance. The leucine-rich repeat and fibronectin type-III domain-containing prot...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2023-10-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/10/e007230.full |
| _version_ | 1827208028944859136 |
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| author | Xu Chen Anze Yu Jiao Hu Liangmin Fu Gaowei Huang Dingshan Deng Mingxiao Zhang Yinghan Wang Guannan Shu Lanyu Jing Huihuang Li Taowei Yang Jinhuan Wei Zhenhua Chen Xiongbing Zu Junhang Luo |
| author_facet | Xu Chen Anze Yu Jiao Hu Liangmin Fu Gaowei Huang Dingshan Deng Mingxiao Zhang Yinghan Wang Guannan Shu Lanyu Jing Huihuang Li Taowei Yang Jinhuan Wei Zhenhua Chen Xiongbing Zu Junhang Luo |
| author_sort | Xu Chen |
| collection | DOAJ |
| description | Background Immune checkpoint inhibitor (ICI) therapy improves the survival of patients with advanced bladder cancer (BLCA); however, its overall effectiveness is limited, and many patients still develop immunotherapy resistance. The leucine-rich repeat and fibronectin type-III domain-containing protein (LRFN) family has previously been implicated in regulating brain dysfunction; however, the mechanisms underlying the effect of LRFN2 on the tumor microenvironment (TME) and immunotherapy remain unclear.Methods Here we combined bulk RNA sequencing, single-cell RNA sequencing, ProcartaPlex multiple immunoassays, functional experiments, and TissueFAXS panoramic tissue quantification assays to demonstrate that LRFN2 shapes a non-inflammatory TME in BLCA.Results First, comprehensive multiomics analysis identified LRFN2 as a novel immunosuppressive target specific to BLCA. We found that tumor-intrinsic LRFN2 inhibited the recruitment and functional transition of CD8+ T cells by reducing the secretion of pro-inflammatory cytokines and chemokines, and this mechanism was verified in vitro and in vivo. LRFN2 restrained antitumor immunity by inhibiting the infiltration, proliferation, and differentiation of CD8+ T cells in vitro. Furthermore, a spatial exclusivity relationship was observed between LRFN2+ tumor cells and CD8+ T cells and cell markers programmed cell death-1 (PD-1) and T cell factor 1 (TCF-1). Preclinically, LRFN2 knockdown significantly enhanced the efficacy of ICI therapy. Clinically, LRFN2 can predict immunotherapy responses in real-world and public immunotherapy cohorts. Our results reveal a new role for LRFN2 in tumor immune evasion by regulating chemokine secretion and inhibiting CD8+ T-cell recruitment and functional transition.Conclusions Thus, LRFN2 represents a new target that can be combined with ICIs to provide a potential treatment option for BLCA. |
| first_indexed | 2024-03-11T13:58:34Z |
| format | Article |
| id | doaj.art-dc417e98e159438b8aa2468f80282aab |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2025-03-21T12:49:27Z |
| publishDate | 2023-10-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-dc417e98e159438b8aa2468f80282aab2024-06-27T00:50:10ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-10-01111010.1136/jitc-2023-007230Bladder cancer intrinsic LRFN2 drives anticancer immunotherapy resistance by attenuating CD8+ T cell infiltration and functional transitionXu Chen0Anze Yu1Jiao Hu2Liangmin Fu3Gaowei Huang4Dingshan Deng5Mingxiao Zhang6Yinghan Wang7Guannan Shu8Lanyu Jing9Huihuang Li10Taowei Yang11Jinhuan Wei12Zhenhua Chen13Xiongbing Zu14Junhang Luo15Department of Urology, Sun Yat-sen University First Affiliated Hospital, Guangzhou, Guangdong, ChinaDepartment of Urology, Sun Yat-sen University First Affiliated Hospital, Guangzhou, Guangdong, ChinaDepartment of Urology, Xiangya Hospital Central South University, Changsha, Hunan, ChinaDepartment of Urology, Sun Yat-sen University First Affiliated Hospital, Guangzhou, Guangdong, ChinaDepartment of Urology, Sun Yat-sen University First Affiliated Hospital, Guangzhou, Guangdong, ChinaDepartment of Urology, Xiangya Hospital Central South University, Changsha, Hunan, ChinaDepartment of Urology, Sun Yat-sen University First Affiliated Hospital, Guangzhou, Guangdong, ChinaDepartment of Urology, Sun Yat-sen University First Affiliated Hospital, Guangzhou, Guangdong, ChinaDepartment of Urology, Sun Yat-sen University First Affiliated Hospital, Guangzhou, Guangdong, ChinaDepartment of Breast Surgery, Sun Yat-sen University First Affiliated Hospital, Guangzhou, Guangdong, ChinaDepartment of Urology, Xiangya Hospital Central South University, Changsha, Hunan, ChinaDepartment of Urology, Sun Yat-sen University First Affiliated Hospital, Guangzhou, Guangdong, ChinaDepartment of Urology, Sun Yat-sen University First Affiliated Hospital, Guangzhou, Guangdong, ChinaDepartment of Urology, Sun Yat-sen University First Affiliated Hospital, Guangzhou, Guangdong, ChinaDepartment of Urology, Xiangya Hospital Central South University, Changsha, Hunan, ChinaDepartment of Urology, Sun Yat-sen University First Affiliated Hospital, Guangzhou, Guangdong, ChinaBackground Immune checkpoint inhibitor (ICI) therapy improves the survival of patients with advanced bladder cancer (BLCA); however, its overall effectiveness is limited, and many patients still develop immunotherapy resistance. The leucine-rich repeat and fibronectin type-III domain-containing protein (LRFN) family has previously been implicated in regulating brain dysfunction; however, the mechanisms underlying the effect of LRFN2 on the tumor microenvironment (TME) and immunotherapy remain unclear.Methods Here we combined bulk RNA sequencing, single-cell RNA sequencing, ProcartaPlex multiple immunoassays, functional experiments, and TissueFAXS panoramic tissue quantification assays to demonstrate that LRFN2 shapes a non-inflammatory TME in BLCA.Results First, comprehensive multiomics analysis identified LRFN2 as a novel immunosuppressive target specific to BLCA. We found that tumor-intrinsic LRFN2 inhibited the recruitment and functional transition of CD8+ T cells by reducing the secretion of pro-inflammatory cytokines and chemokines, and this mechanism was verified in vitro and in vivo. LRFN2 restrained antitumor immunity by inhibiting the infiltration, proliferation, and differentiation of CD8+ T cells in vitro. Furthermore, a spatial exclusivity relationship was observed between LRFN2+ tumor cells and CD8+ T cells and cell markers programmed cell death-1 (PD-1) and T cell factor 1 (TCF-1). Preclinically, LRFN2 knockdown significantly enhanced the efficacy of ICI therapy. Clinically, LRFN2 can predict immunotherapy responses in real-world and public immunotherapy cohorts. Our results reveal a new role for LRFN2 in tumor immune evasion by regulating chemokine secretion and inhibiting CD8+ T-cell recruitment and functional transition.Conclusions Thus, LRFN2 represents a new target that can be combined with ICIs to provide a potential treatment option for BLCA.https://jitc.bmj.com/content/11/10/e007230.full |
| spellingShingle | Xu Chen Anze Yu Jiao Hu Liangmin Fu Gaowei Huang Dingshan Deng Mingxiao Zhang Yinghan Wang Guannan Shu Lanyu Jing Huihuang Li Taowei Yang Jinhuan Wei Zhenhua Chen Xiongbing Zu Junhang Luo Bladder cancer intrinsic LRFN2 drives anticancer immunotherapy resistance by attenuating CD8+ T cell infiltration and functional transition Journal for ImmunoTherapy of Cancer |
| title | Bladder cancer intrinsic LRFN2 drives anticancer immunotherapy resistance by attenuating CD8+ T cell infiltration and functional transition |
| title_full | Bladder cancer intrinsic LRFN2 drives anticancer immunotherapy resistance by attenuating CD8+ T cell infiltration and functional transition |
| title_fullStr | Bladder cancer intrinsic LRFN2 drives anticancer immunotherapy resistance by attenuating CD8+ T cell infiltration and functional transition |
| title_full_unstemmed | Bladder cancer intrinsic LRFN2 drives anticancer immunotherapy resistance by attenuating CD8+ T cell infiltration and functional transition |
| title_short | Bladder cancer intrinsic LRFN2 drives anticancer immunotherapy resistance by attenuating CD8+ T cell infiltration and functional transition |
| title_sort | bladder cancer intrinsic lrfn2 drives anticancer immunotherapy resistance by attenuating cd8 t cell infiltration and functional transition |
| url | https://jitc.bmj.com/content/11/10/e007230.full |
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