
Anticancer effects of ikarugamycin and astemizole identified in a screen for stimulators of cellular immune responses
- Author
- Shuai Zhang, Liwei Zhao, Mengfei Guo, Peng Liu, Sijing Li, Wei Xie (UGent) , Ai-Ling Tian, Jonathan G. Pol, Hui Chen, Hui Pan, Misha Mao, Yumei Li, Laurence Zitvogel, Yang Jin, Oliver Kepp and Guido Kroemer
- Organization
- Abstract
- Background: Most immunotherapies approved for clinical use rely on the use of recombinant proteins and cell-based approaches, rendering their manufacturing expensive and logistics onerous. The identification of novel small molecule immunotherapeutic agents might overcome such limitations. Method: For immunopharmacological screening campaigns, we built an artificial miniature immune system in which dendritic cells (DCs) derived from immature precursors present MHC (major histocompatibility complex) class I-restricted antigen to a T-cell hybridoma that then secretes interleukin-2 (IL-2). Results: The screening of three drug libraries relevant to known signaling pathways, FDA (Food and Drug Administration)-approved drugs and neuroendocrine factors yielded two major hits, astemizole and ikarugamycin. Mechanistically, ikarugamycin turned out to act on DCs to inhibit hexokinase 2, hence stimulating their antigen presenting potential. In contrast, astemizole acts as a histamine H1 receptor (H1R1) antagonist to activate T cells in a non-specific, DC-independent fashion. Astemizole induced the production of IL-2 and interferon-& gamma; (IFN-& gamma;) by CD4(+) and CD8(+) T cells both in vitro and in vivo. Both ikarugamycin and astemizole improved the anticancer activity of the immunogenic chemotherapeutic agent oxaliplatin in a T cell-dependent fashion. Of note, astemizole enhanced the CD8(+)/Foxp3(+) ratio in the tumor immune infiltrate as well as IFN-& gamma; production by local CD8(+) T lymphocytes. In patients with cancer, high H1R1 expression correlated with low infiltration by TH1 cells, as well as with signs of T-cell exhaustion. The combination of astemizole and oxaliplatin was able to cure the majority of mice bearing orthotopic non-small cell lung cancers (NSCLC), then inducing a state of protective long-term immune memory. The NSCLC-eradicating effect of astemizole plus oxaliplatin was lost on depletion of either CD4(+) or CD8(+) T cells, as well as on neutralization of IFN-& gamma;. Conclusions: These findings underscore the potential utility of this screening system for the identification of immunostimulatory drugs with anticancer effects.
- Keywords
- Antigen Presentation, Dendritic Cells, Immunity, Immunologic Memory, Immunotherapy, CALRETICULIN EXPOSURE, IMMUNOGENICITY, CELLS
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Citation
Please use this url to cite or link to this publication: http://hdl.handle.net/1854/LU-01HNFM14J595C052M190EHZ6TH
- MLA
- Zhang, Shuai, et al. “Anticancer Effects of Ikarugamycin and Astemizole Identified in a Screen for Stimulators of Cellular Immune Responses.” JOURNAL FOR IMMUNOTHERAPY OF CANCER, vol. 11, no. 7, 2023, doi:10.1136/jitc-2023-006785.
- APA
- Zhang, S., Zhao, L., Guo, M., Liu, P., Li, S., Xie, W., … Kroemer, G. (2023). Anticancer effects of ikarugamycin and astemizole identified in a screen for stimulators of cellular immune responses. JOURNAL FOR IMMUNOTHERAPY OF CANCER, 11(7). https://doi.org/10.1136/jitc-2023-006785
- Chicago author-date
- Zhang, Shuai, Liwei Zhao, Mengfei Guo, Peng Liu, Sijing Li, Wei Xie, Ai-Ling Tian, et al. 2023. “Anticancer Effects of Ikarugamycin and Astemizole Identified in a Screen for Stimulators of Cellular Immune Responses.” JOURNAL FOR IMMUNOTHERAPY OF CANCER 11 (7). https://doi.org/10.1136/jitc-2023-006785.
- Chicago author-date (all authors)
- Zhang, Shuai, Liwei Zhao, Mengfei Guo, Peng Liu, Sijing Li, Wei Xie, Ai-Ling Tian, Jonathan G. Pol, Hui Chen, Hui Pan, Misha Mao, Yumei Li, Laurence Zitvogel, Yang Jin, Oliver Kepp, and Guido Kroemer. 2023. “Anticancer Effects of Ikarugamycin and Astemizole Identified in a Screen for Stimulators of Cellular Immune Responses.” JOURNAL FOR IMMUNOTHERAPY OF CANCER 11 (7). doi:10.1136/jitc-2023-006785.
- Vancouver
- 1.Zhang S, Zhao L, Guo M, Liu P, Li S, Xie W, et al. Anticancer effects of ikarugamycin and astemizole identified in a screen for stimulators of cellular immune responses. JOURNAL FOR IMMUNOTHERAPY OF CANCER. 2023;11(7).
- IEEE
- [1]S. Zhang et al., “Anticancer effects of ikarugamycin and astemizole identified in a screen for stimulators of cellular immune responses,” JOURNAL FOR IMMUNOTHERAPY OF CANCER, vol. 11, no. 7, 2023.
@article{01HNFM14J595C052M190EHZ6TH, abstract = {{Background: Most immunotherapies approved for clinical use rely on the use of recombinant proteins and cell-based approaches, rendering their manufacturing expensive and logistics onerous. The identification of novel small molecule immunotherapeutic agents might overcome such limitations. Method: For immunopharmacological screening campaigns, we built an artificial miniature immune system in which dendritic cells (DCs) derived from immature precursors present MHC (major histocompatibility complex) class I-restricted antigen to a T-cell hybridoma that then secretes interleukin-2 (IL-2). Results: The screening of three drug libraries relevant to known signaling pathways, FDA (Food and Drug Administration)-approved drugs and neuroendocrine factors yielded two major hits, astemizole and ikarugamycin. Mechanistically, ikarugamycin turned out to act on DCs to inhibit hexokinase 2, hence stimulating their antigen presenting potential. In contrast, astemizole acts as a histamine H1 receptor (H1R1) antagonist to activate T cells in a non-specific, DC-independent fashion. Astemizole induced the production of IL-2 and interferon-& gamma; (IFN-& gamma;) by CD4(+) and CD8(+) T cells both in vitro and in vivo. Both ikarugamycin and astemizole improved the anticancer activity of the immunogenic chemotherapeutic agent oxaliplatin in a T cell-dependent fashion. Of note, astemizole enhanced the CD8(+)/Foxp3(+) ratio in the tumor immune infiltrate as well as IFN-& gamma; production by local CD8(+) T lymphocytes. In patients with cancer, high H1R1 expression correlated with low infiltration by TH1 cells, as well as with signs of T-cell exhaustion. The combination of astemizole and oxaliplatin was able to cure the majority of mice bearing orthotopic non-small cell lung cancers (NSCLC), then inducing a state of protective long-term immune memory. The NSCLC-eradicating effect of astemizole plus oxaliplatin was lost on depletion of either CD4(+) or CD8(+) T cells, as well as on neutralization of IFN-& gamma;. Conclusions: These findings underscore the potential utility of this screening system for the identification of immunostimulatory drugs with anticancer effects.}}, articleno = {{e006785}}, author = {{Zhang, Shuai and Zhao, Liwei and Guo, Mengfei and Liu, Peng and Li, Sijing and Xie, Wei and Tian, Ai-Ling and Pol, Jonathan G. and Chen, Hui and Pan, Hui and Mao, Misha and Li, Yumei and Zitvogel, Laurence and Jin, Yang and Kepp, Oliver and Kroemer, Guido}}, issn = {{2051-1426}}, journal = {{JOURNAL FOR IMMUNOTHERAPY OF CANCER}}, keywords = {{Antigen Presentation,Dendritic Cells,Immunity,Immunologic Memory,Immunotherapy,CALRETICULIN EXPOSURE,IMMUNOGENICITY,CELLS}}, language = {{eng}}, number = {{7}}, pages = {{17}}, title = {{Anticancer effects of ikarugamycin and astemizole identified in a screen for stimulators of cellular immune responses}}, url = {{http://doi.org/10.1136/jitc-2023-006785}}, volume = {{11}}, year = {{2023}}, }
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