RAC2 inhibition enhances tumor sensitivity to NK cell-mediated cytotoxicity
Background Natural killer (NK) cells are recognized for their ability to kill tumor cells for tumor control, but tumor cells often develop resistance to evade NK cell-mediated cytotoxicity. Identification of molecular mechanisms by which tumor cells evade from NK cell-mediated killing may offer nove...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2025-05-01
|
| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/5/e010931.full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849325060391698432 |
|---|---|
| author | Lin Li Hui Guo Jie Hu Lei Cui Zining Wang Feifei Xu Xiaojuan Wang Huanling Zhang Chunyuan Xie Yongxiang Liu Xiaojun Xia Zixuan Guo Heping Li Tiantian Wang Ruhui Yao Huan Jin Yanxun Lin |
| author_facet | Lin Li Hui Guo Jie Hu Lei Cui Zining Wang Feifei Xu Xiaojuan Wang Huanling Zhang Chunyuan Xie Yongxiang Liu Xiaojun Xia Zixuan Guo Heping Li Tiantian Wang Ruhui Yao Huan Jin Yanxun Lin |
| author_sort | Lin Li |
| collection | DOAJ |
| description | Background Natural killer (NK) cells are recognized for their ability to kill tumor cells for tumor control, but tumor cells often develop resistance to evade NK cell-mediated cytotoxicity. Identification of molecular mechanisms by which tumor cells evade from NK cell-mediated killing may offer novel therapeutic strategies for potentiating NK-based cancer immunotherapy.Methods An in vitro tumor-NK cell co-culture system was employed to identify the most significantly altered genes in tumor cells following NK cell interaction. The cell death rate of tumor cells by NK cell exposure was quantified using flow cytometry. EL4 and HCT116 tumor models in C57BL/6, BALB/c-nu, and NOD/SCID mice were used for evaluating tumor growth differences induced by Rac2 knockdown or knockout. The cellular and molecular impact of Rac2 knockdown or knockout on the sensitivity of tumor cells to NK cell-mediated cytotoxicity was assessed using quantitative PCR, immunofluorescence, and mutation analysis.Results By screening expression levels of the Ras homology (Rho) GTPase family genes in tumor cells after co-culture with NK cells, we identified RAC2 as a key regulator of tumor cell resistance to NK cell-mediated cytotoxicity among the Rho GTPase family members. Furthermore, knockout of RAC2 in human colorectal cancer cells leads to increased tumor susceptibility to NK cell-mediated cytotoxicity in a xenograft tumor model. Mechanistically, the absence of RAC2 enhances tumor cell sensitivity to NK cell-mediated killing by facilitating cell–cell contact.Conclusions These findings indicate that the inhibition of RAC2 in tumor cells substantially enhances their susceptibility to NK cell-mediated cytotoxicity, thereby providing a potential therapeutic target for optimizing NK cell therapy. |
| format | Article |
| id | doaj-art-bd85d757449c42ce94f0aa95d186c060 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-bd85d757449c42ce94f0aa95d186c0602025-08-20T03:48:31ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-05-0113510.1136/jitc-2024-010931RAC2 inhibition enhances tumor sensitivity to NK cell-mediated cytotoxicityLin Li0Hui Guo1Jie Hu2Lei Cui3Zining Wang4Feifei Xu5Xiaojuan Wang6Huanling Zhang7Chunyuan Xie8Yongxiang Liu9Xiaojun Xia10Zixuan Guo11Heping Li12Tiantian Wang13Ruhui Yao14Huan Jin15Yanxun Lin161 Department of Experiment Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China1 Department of Experiment Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China2 Department of Medical Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China1 Department of Experiment Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China1 Department of Experiment Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China3 Department of Oncology, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China1 Department of Experiment Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China4 Guangzhou National Laboratory, Guangzhou, Guangdong, China1 Department of Experiment Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China4 Guangzhou National Laboratory, Guangzhou, Guangdong, China1 Department of Experiment Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China1 Department of Experiment Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China5 Department of Medical Oncology, Sun Yat-Sen Memorial Hospital, Guangzhou, Guangdong, China1 Department of Experiment Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China1 Department of Experiment Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China1 Department of Experiment Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China1 Department of Experiment Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, ChinaBackground Natural killer (NK) cells are recognized for their ability to kill tumor cells for tumor control, but tumor cells often develop resistance to evade NK cell-mediated cytotoxicity. Identification of molecular mechanisms by which tumor cells evade from NK cell-mediated killing may offer novel therapeutic strategies for potentiating NK-based cancer immunotherapy.Methods An in vitro tumor-NK cell co-culture system was employed to identify the most significantly altered genes in tumor cells following NK cell interaction. The cell death rate of tumor cells by NK cell exposure was quantified using flow cytometry. EL4 and HCT116 tumor models in C57BL/6, BALB/c-nu, and NOD/SCID mice were used for evaluating tumor growth differences induced by Rac2 knockdown or knockout. The cellular and molecular impact of Rac2 knockdown or knockout on the sensitivity of tumor cells to NK cell-mediated cytotoxicity was assessed using quantitative PCR, immunofluorescence, and mutation analysis.Results By screening expression levels of the Ras homology (Rho) GTPase family genes in tumor cells after co-culture with NK cells, we identified RAC2 as a key regulator of tumor cell resistance to NK cell-mediated cytotoxicity among the Rho GTPase family members. Furthermore, knockout of RAC2 in human colorectal cancer cells leads to increased tumor susceptibility to NK cell-mediated cytotoxicity in a xenograft tumor model. Mechanistically, the absence of RAC2 enhances tumor cell sensitivity to NK cell-mediated killing by facilitating cell–cell contact.Conclusions These findings indicate that the inhibition of RAC2 in tumor cells substantially enhances their susceptibility to NK cell-mediated cytotoxicity, thereby providing a potential therapeutic target for optimizing NK cell therapy.https://jitc.bmj.com/content/13/5/e010931.full |
| spellingShingle | Lin Li Hui Guo Jie Hu Lei Cui Zining Wang Feifei Xu Xiaojuan Wang Huanling Zhang Chunyuan Xie Yongxiang Liu Xiaojun Xia Zixuan Guo Heping Li Tiantian Wang Ruhui Yao Huan Jin Yanxun Lin RAC2 inhibition enhances tumor sensitivity to NK cell-mediated cytotoxicity Journal for ImmunoTherapy of Cancer |
| title | RAC2 inhibition enhances tumor sensitivity to NK cell-mediated cytotoxicity |
| title_full | RAC2 inhibition enhances tumor sensitivity to NK cell-mediated cytotoxicity |
| title_fullStr | RAC2 inhibition enhances tumor sensitivity to NK cell-mediated cytotoxicity |
| title_full_unstemmed | RAC2 inhibition enhances tumor sensitivity to NK cell-mediated cytotoxicity |
| title_short | RAC2 inhibition enhances tumor sensitivity to NK cell-mediated cytotoxicity |
| title_sort | rac2 inhibition enhances tumor sensitivity to nk cell mediated cytotoxicity |
| url | https://jitc.bmj.com/content/13/5/e010931.full |
| work_keys_str_mv | AT linli rac2inhibitionenhancestumorsensitivitytonkcellmediatedcytotoxicity AT huiguo rac2inhibitionenhancestumorsensitivitytonkcellmediatedcytotoxicity AT jiehu rac2inhibitionenhancestumorsensitivitytonkcellmediatedcytotoxicity AT leicui rac2inhibitionenhancestumorsensitivitytonkcellmediatedcytotoxicity AT ziningwang rac2inhibitionenhancestumorsensitivitytonkcellmediatedcytotoxicity AT feifeixu rac2inhibitionenhancestumorsensitivitytonkcellmediatedcytotoxicity AT xiaojuanwang rac2inhibitionenhancestumorsensitivitytonkcellmediatedcytotoxicity AT huanlingzhang rac2inhibitionenhancestumorsensitivitytonkcellmediatedcytotoxicity AT chunyuanxie rac2inhibitionenhancestumorsensitivitytonkcellmediatedcytotoxicity AT yongxiangliu rac2inhibitionenhancestumorsensitivitytonkcellmediatedcytotoxicity AT xiaojunxia rac2inhibitionenhancestumorsensitivitytonkcellmediatedcytotoxicity AT zixuanguo rac2inhibitionenhancestumorsensitivitytonkcellmediatedcytotoxicity AT hepingli rac2inhibitionenhancestumorsensitivitytonkcellmediatedcytotoxicity AT tiantianwang rac2inhibitionenhancestumorsensitivitytonkcellmediatedcytotoxicity AT ruhuiyao rac2inhibitionenhancestumorsensitivitytonkcellmediatedcytotoxicity AT huanjin rac2inhibitionenhancestumorsensitivitytonkcellmediatedcytotoxicity AT yanxunlin rac2inhibitionenhancestumorsensitivitytonkcellmediatedcytotoxicity |