2. Academic Validation
  3. Anticancer effects of ikarugamycin and astemizole identified in a screen for stimulators of cellular immune responses

Anticancer effects of ikarugamycin and astemizole identified in a screen for stimulators of cellular immune responses

  • J Immunother Cancer. 2023 Jul;11(7):e006785. doi: 10.1136/jitc-2023-006785.
Shuai Zhang # 1 2 3 4,  Liwei Zhao # 1 2,  Mengfei Guo # 3,  Peng Liu # 1 2,  Sijing Li 1 2 4,  Wei Xie 5 6,  Ai-Ling Tian 1 2,  Jonathan G Pol 1 2,  Hui Chen 1 2 4,  Hui Pan 1 2 4,  Misha Mao 1 2 4 7,  Yumei Li 3,  Laurence Zitvogel 8 9,  Yang Jin 10,  Oliver Kepp 11 2,  Guido Kroemer 11 2 12
Affiliations

Affiliations

  • 1 Metabolomics and Cell Biology Platforms, Gustave Roussy, Villejuif, France.
  • 2 Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France.
  • 3 Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
  • 4 Faculté de Médecine, Université de Paris Saclay, Kremlin Bicêtre, France.
  • 5 Cell death and Inflammation Unit, VIB-UGent Center for Inflammation Research, Ghent, Belgium.
  • 6 Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
  • 7 Surgical Oncology Department, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China.
  • 8 INSERM U1015, Equipe labellisée par la Ligue contre le cancer, Gustave Roussy, Villjuif, France.
  • 9 ClinicObiome, Gustave-Roussy, Villejuif, France.
  • 10 Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China captain.olsen@gmail.com kroemer@orange.fr whuhjy@126.com.
  • 11 Metabolomics and Cell Biology Platforms, Gustave Roussy, Villejuif, France captain.olsen@gmail.com kroemer@orange.fr whuhjy@126.com.
  • 12 Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
  • # Contributed equally.
PMID: 37419511 DOI: 10.1136/jitc-2023-006785
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-γ (IFN-γ) 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-γ 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-γ.

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.

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