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

Author:

Zhang Shuai,Zhao Liwei,Guo Mengfei,Liu Peng,Li Sijing,Xie WeiORCID,Tian Ai-Ling,Pol Jonathan GORCID,Chen HuiORCID,Pan Hui,Mao Misha,Li Yumei,Zitvogel Laurence,Jin YangORCID,Kepp OliverORCID,Kroemer Guido

Abstract

BackgroundMost 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.MethodFor 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).ResultsThe 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.ConclusionsThese findings underscore the potential utility of this screening system for the identification of immunostimulatory drugs with anticancer effects.

Funder

Wuhan Union Hospital

SIRIC

Cancéropôle Ile-de-France

Fondation pour la Recherche Médicale

Seerave Foundation

Association pour la Recherche sur le Cancer

Mark Foundation For Cancer Research

AMMICa

Institut Universitaire de France

Agence Nationale de la Recherche

Ile de france

H2020 European Research Council

Labex Immuno-Oncology

Institut National Du Cancer

Université de Paris

ELIOR

China Scholarship Council

European Joint Programme on Rare Diseases

European Research Council

Lique contre le cancer

Publisher

BMJ

Subject

Cancer Research,Pharmacology,Oncology,Molecular Medicine,Immunology,Immunology and Allergy

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