Antitumor effect of CAR-T cells targeting transmembrane tumor necrosis factor alpha combined with PD-1 mAb on breast cancers
Background Our previous study showed that transmembrane tumor necrosis factor alpha (tmTNF-α) is overexpressed in primary breast cancers including triple-negative breast cancers (TNBCs). Chimeric antigen receptor engineered-T (CAR-T) cells have been successfully used mainly in B-cell malignancies.Me...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2023-01-01
|
| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/1/e003837.full |
| _version_ | 1797769876171915264 |
|---|---|
| author | Jing Wang Peng Zhang Xiaoxi Zhou Hongping Ba Zigang Dai Zunyue Zhang Bingjiao Yin Zhuoya Li |
| author_facet | Jing Wang Peng Zhang Xiaoxi Zhou Hongping Ba Zigang Dai Zunyue Zhang Bingjiao Yin Zhuoya Li |
| author_sort | Jing Wang |
| collection | DOAJ |
| description | Background Our previous study showed that transmembrane tumor necrosis factor alpha (tmTNF-α) is overexpressed in primary breast cancers including triple-negative breast cancers (TNBCs). Chimeric antigen receptor engineered-T (CAR-T) cells have been successfully used mainly in B-cell malignancies.Methods We generated CAR-T cells targeting tmTNF-α but not secreted tumor necrosis factor alpha and assessed the antitumor effect of the CAR-T cells on tmTNF-α-expressing breast cancer cells in vitro and in vivo.Results Our tmTNF-α CAR-T cells showed potent cytotoxicity against tmTNF-α-expressing breast cancer cells but not tmTNF-α-negative tumor cells with increased secretion of interferon gamma (IFN-γ) and interleukin (IL)-2 in vitro. In tmTNF-α-overexpressing TNBC-bearing mice, the tmTNF-α CAR-T therapy induced evident tumor regression, prolonged survival and increased serum concentrations of IFN-γ and IL-2. However, we found thattmTNF-α induced programmed death-ligand 1 (PD-L1) expression through the p38 pathway via TNF receptor (TNFR) and through the NF-κB and AKT pathways via outside-to-inside (reverse) signaling, which might limit the efficacy of the CAR-T cell therapy. Blockage of the PD-L1/programmed death-1 (PD-1) pathway by PD-1 monoclonal antibody significantly enhanced the antitumor effect of the tmTNF-α CAR-T cell therapy in vitro and in vivo, and the combination was effective for antiprimary tumors and had a tendency to increase the antimetastasis effect of the CAR-T cell therapy.Conclusion Our findings suggest a potent antitumor efficacy of the tmTNF-α CAR-T cells that can be enhanced by anti-PD-L1/PD-1 because high PD-L1 expression in TNBC was induced by the tmTNF-α signaling, indicating a promising individual therapy for tmTNF-α-positive breast cancers including TNBC. |
| first_indexed | 2024-03-12T21:14:24Z |
| format | Article |
| id | doaj.art-e47241f84756469cb59d917e2ea6b2b0 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-03-12T21:14:24Z |
| publishDate | 2023-01-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-e47241f84756469cb59d917e2ea6b2b02023-07-30T00:35:07ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-01-0111110.1136/jitc-2021-003837Antitumor effect of CAR-T cells targeting transmembrane tumor necrosis factor alpha combined with PD-1 mAb on breast cancersJing Wang0Peng Zhang1Xiaoxi Zhou2Hongping Ba3Zigang Dai4Zunyue Zhang5Bingjiao Yin6Zhuoya Li76Inner Mongolia Institute of Digestive Diseases, The Second Affiliated Hospital of Baotou Medical College, Baotou, China2 Beijing Key Laboratory for Genetics of Birth Defects, Beijing Pediatric Research Institute, Beijing, ChinaDepartment of Hematology, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Immunology, College of Basic Medicine of Tongji Medical College of Huazhong University of Scince and Technology, Wuhan, Hubei, People`s Republic of ChinaDepartment of Hematology, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Immunology, College of Basic Medicine of Tongji Medical College of Huazhong University of Scince and Technology, Wuhan, Hubei, People`s Republic of ChinaDepartment of Immunology, College of Basic Medicine of Tongji Medical College of Huazhong University of Scince and Technology, Wuhan, Hubei, People`s Republic of ChinaDepartment of Immunology, College of Basic Medicine of Tongji Medical College of Huazhong University of Scince and Technology, Wuhan, Hubei, People`s Republic of ChinaBackground Our previous study showed that transmembrane tumor necrosis factor alpha (tmTNF-α) is overexpressed in primary breast cancers including triple-negative breast cancers (TNBCs). Chimeric antigen receptor engineered-T (CAR-T) cells have been successfully used mainly in B-cell malignancies.Methods We generated CAR-T cells targeting tmTNF-α but not secreted tumor necrosis factor alpha and assessed the antitumor effect of the CAR-T cells on tmTNF-α-expressing breast cancer cells in vitro and in vivo.Results Our tmTNF-α CAR-T cells showed potent cytotoxicity against tmTNF-α-expressing breast cancer cells but not tmTNF-α-negative tumor cells with increased secretion of interferon gamma (IFN-γ) and interleukin (IL)-2 in vitro. In tmTNF-α-overexpressing TNBC-bearing mice, the tmTNF-α CAR-T therapy induced evident tumor regression, prolonged survival and increased serum concentrations of IFN-γ and IL-2. However, we found thattmTNF-α induced programmed death-ligand 1 (PD-L1) expression through the p38 pathway via TNF receptor (TNFR) and through the NF-κB and AKT pathways via outside-to-inside (reverse) signaling, which might limit the efficacy of the CAR-T cell therapy. Blockage of the PD-L1/programmed death-1 (PD-1) pathway by PD-1 monoclonal antibody significantly enhanced the antitumor effect of the tmTNF-α CAR-T cell therapy in vitro and in vivo, and the combination was effective for antiprimary tumors and had a tendency to increase the antimetastasis effect of the CAR-T cell therapy.Conclusion Our findings suggest a potent antitumor efficacy of the tmTNF-α CAR-T cells that can be enhanced by anti-PD-L1/PD-1 because high PD-L1 expression in TNBC was induced by the tmTNF-α signaling, indicating a promising individual therapy for tmTNF-α-positive breast cancers including TNBC.https://jitc.bmj.com/content/11/1/e003837.full |
| spellingShingle | Jing Wang Peng Zhang Xiaoxi Zhou Hongping Ba Zigang Dai Zunyue Zhang Bingjiao Yin Zhuoya Li Antitumor effect of CAR-T cells targeting transmembrane tumor necrosis factor alpha combined with PD-1 mAb on breast cancers Journal for ImmunoTherapy of Cancer |
| title | Antitumor effect of CAR-T cells targeting transmembrane tumor necrosis factor alpha combined with PD-1 mAb on breast cancers |
| title_full | Antitumor effect of CAR-T cells targeting transmembrane tumor necrosis factor alpha combined with PD-1 mAb on breast cancers |
| title_fullStr | Antitumor effect of CAR-T cells targeting transmembrane tumor necrosis factor alpha combined with PD-1 mAb on breast cancers |
| title_full_unstemmed | Antitumor effect of CAR-T cells targeting transmembrane tumor necrosis factor alpha combined with PD-1 mAb on breast cancers |
| title_short | Antitumor effect of CAR-T cells targeting transmembrane tumor necrosis factor alpha combined with PD-1 mAb on breast cancers |
| title_sort | antitumor effect of car t cells targeting transmembrane tumor necrosis factor alpha combined with pd 1 mab on breast cancers |
| url | https://jitc.bmj.com/content/11/1/e003837.full |
| work_keys_str_mv | AT jingwang antitumoreffectofcartcellstargetingtransmembranetumornecrosisfactoralphacombinedwithpd1mabonbreastcancers AT pengzhang antitumoreffectofcartcellstargetingtransmembranetumornecrosisfactoralphacombinedwithpd1mabonbreastcancers AT xiaoxizhou antitumoreffectofcartcellstargetingtransmembranetumornecrosisfactoralphacombinedwithpd1mabonbreastcancers AT hongpingba antitumoreffectofcartcellstargetingtransmembranetumornecrosisfactoralphacombinedwithpd1mabonbreastcancers AT zigangdai antitumoreffectofcartcellstargetingtransmembranetumornecrosisfactoralphacombinedwithpd1mabonbreastcancers AT zunyuezhang antitumoreffectofcartcellstargetingtransmembranetumornecrosisfactoralphacombinedwithpd1mabonbreastcancers AT bingjiaoyin antitumoreffectofcartcellstargetingtransmembranetumornecrosisfactoralphacombinedwithpd1mabonbreastcancers AT zhuoyali antitumoreffectofcartcellstargetingtransmembranetumornecrosisfactoralphacombinedwithpd1mabonbreastcancers |