BMC medicine · 2026
Targeting CCR7-KMT2D enhances CAR-T cell efficacy by suppressing therapy-induced senescence in B-cell non-Hodgkin lymphoma.
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Li Jinlan, Huang Keke, Wang Huiping, Chen Wanjia, Zhang Yajie, Jiang Shanyue, Cao Nengneng, Zhang Wanqiu, Liu Zelin, Chen Jiawen, Chen Dandan, Yang Ziye, Tao Qianshan, Liu Chaohong, Zhai Zhimin, An Furun, Wang Jiyu
Аннотация
BACKGROUND: The efficacy of anti-CD19 Chimeric Antigen Receptor (CAR) T-cell therapy has been demonstrated in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (B-NHL). However, therapy-induced senescence (TIS) has been identified as a novel resistance mechanism, potentially exacerbating immunosuppression and impairing CAR-T cell function.
METHODS: Raji and SU-DHL-2 cells were treated with 40 nM doxorubicin (Dox) for 72 h to induce TIS, and CCR7 was inhibited with 10 µg/mL Cap-100. Cellular senescence was assessed by SA-β-Gal staining and flow cytometry; proliferation and apoptosis by CCK-8 and Annexin V/PI, respectively. CAR-T cytotoxicity was evaluated via flow cytometry. CCR7 expression on T cells from B-NHL patients and healthy controls was measured. Lentiviral transduction regulated CCR7 expression; protein expression and interactions were analyzed by Western blot and Co-IP. NF-κB and ARHGAP/RhoA pathways were inhibited using GS143 and Y27632, respectively.
RESULTS: CCR7 overexpression enhanced SASP, while knockdown attenuated it. In the Dox-induced TIS model, KMT2D decreased, whereas H3K9me3, CCR7, and LGALS9 increased; CCR7 inhibition reversed these changes. Cap-100 improved CD19 CAR T killing by alleviating exhaustion in co-culture. Mechanistically, Cap-100 stabilized IκBα to inhibit NFκB, and inhibition of NFκB or ROCK reversed pro-senescence. Cap-100 reduced T cell proliferation but did not affect apoptosis or exhaustion. Clinically, CCR7 was lower on T cells from B NHL patients than healthy controls, and higher CCR7 correlated with better T cell quality. Transcriptomics showed Dox activated TIM3/Galectin 9 and PD- 1/PD-L1 pathways, while Dox + Cap-100 suppressed them. Co-IP confirmed interactions among CCR7, KMT2D, and LGALS9. Collectively, Dox induced TIS to upregulate CCR7, increasing SASP and LGALS9, which interacted with TIM-3, causing immune cell exhaustion and reducing killing efficiency; CCR7 blockade reversed this state and enhanced cytotoxicity.
CONCLUSIONS: Our findings demonstrate that blockade of KMT2D-CCR7-mediated senescence enhances CD19 CAR-T cell anti-tumor activity in B-NHL.
METHODS: Raji and SU-DHL-2 cells were treated with 40 nM doxorubicin (Dox) for 72 h to induce TIS, and CCR7 was inhibited with 10 µg/mL Cap-100. Cellular senescence was assessed by SA-β-Gal staining and flow cytometry; proliferation and apoptosis by CCK-8 and Annexin V/PI, respectively. CAR-T cytotoxicity was evaluated via flow cytometry. CCR7 expression on T cells from B-NHL patients and healthy controls was measured. Lentiviral transduction regulated CCR7 expression; protein expression and interactions were analyzed by Western blot and Co-IP. NF-κB and ARHGAP/RhoA pathways were inhibited using GS143 and Y27632, respectively.
RESULTS: CCR7 overexpression enhanced SASP, while knockdown attenuated it. In the Dox-induced TIS model, KMT2D decreased, whereas H3K9me3, CCR7, and LGALS9 increased; CCR7 inhibition reversed these changes. Cap-100 improved CD19 CAR T killing by alleviating exhaustion in co-culture. Mechanistically, Cap-100 stabilized IκBα to inhibit NFκB, and inhibition of NFκB or ROCK reversed pro-senescence. Cap-100 reduced T cell proliferation but did not affect apoptosis or exhaustion. Clinically, CCR7 was lower on T cells from B NHL patients than healthy controls, and higher CCR7 correlated with better T cell quality. Transcriptomics showed Dox activated TIM3/Galectin 9 and PD- 1/PD-L1 pathways, while Dox + Cap-100 suppressed them. Co-IP confirmed interactions among CCR7, KMT2D, and LGALS9. Collectively, Dox induced TIS to upregulate CCR7, increasing SASP and LGALS9, which interacted with TIM-3, causing immune cell exhaustion and reducing killing efficiency; CCR7 blockade reversed this state and enhanced cytotoxicity.
CONCLUSIONS: Our findings demonstrate that blockade of KMT2D-CCR7-mediated senescence enhances CD19 CAR-T cell anti-tumor activity in B-NHL.