IGF1 receptor inhibition amplifies the effects of cancer drugs by autophagy and immune-dependent mechanisms

  • J Immunother Cancer. 2021 Jun;9(6):e002722. doi: 10.1136/jitc-2021-002722.
Qi Wu  1  2  3 ,  Ai-Ling Tian  2  3  4 ,  Bei Li  5 ,  Marion Leduc  2  3 ,  Sabrina Forveille  2  3 ,  Peter Hamley  6 ,  Warren Galloway  6 ,  Wei Xie  2  3 ,  Peng Liu  2  3 ,  Liwei Zhao  2  3 ,  Shuai Zhang  2  3  4 ,  Pan Hui  2  3  4 ,  Frank Madeo  7  8  9 ,  Yi Tu  10 ,  Oliver Kepp  11  3 ,  Guido Kroemer  11  3  12  13  14
Affiliations
  • 1. Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
  • 2. Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France.
  • 3. Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Université Paris Saclay, Villejuif, France.
  • 4. Faculty of Medicine, Université Paris Saclay, Kremlin Bicêtre, France.
  • 5. Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
  • 6. Samsara Therapeutics Ltd, Oxford, UK.
  • 7. Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria.
  • 8. BioTechMed-Graz, Graz, Austria.
  • 9. Field of Excellence BioHealth, University of Graz, Graz, Austria.
  • 10. Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China [email protected] [email protected] [email protected].
  • 11. Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France [email protected] [email protected] [email protected].
  • 12. Suzhou Institute for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, Jiangsu, China.
  • 13. Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
  • 14. Karolinska Institutet, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden.
PMID: 34127545 DOI: 10.1136/jitc-2021-002722
Abstract

Background: Pharmacological Autophagy enhancement constitutes a preclinically validated strategy for preventing or treating most major age-associated diseases. Driven by this consideration, we performed a high-content/high-throughput screen on 65 000 distinct compounds on a robotized fluorescence microscopy platform to identify novel Autophagy inducers.

Results: Here, we report the discovery of picropodophyllin (PPP) as a potent inducer of autophagic flux that acts on-target, as an inhibitor of the tyrosine kinase activity of the insulin-like growth factor-1 receptor (IGF1R). Thus, PPP lost its autophagy-stimulatory activity in cells engineered to lack IGF1R or to express a constitutively active Akt serine/threonine kinase 1 (Akt1) mutant. When administered to cancer-bearing mice, PPP improved the therapeutic efficacy of chemoimmunotherapy with a combination of immunogenic cytotoxicants and programmed cell death 1 (PDCD1, better known as PD-1) blockade. These PPP effects were lost when tumors were rendered PPP-insensitive or autophagy-incompetent. In combination with chemotherapy, PPP enhanced the infiltration of tumors by cytotoxic T lymphocytes, while reducing regulatory T cells. In human triple-negative breast Cancer patients, the activating phosphorylation of IGF1R correlated with inhibited Autophagy, an unfavorable local immune profile, and poor prognosis.

Conclusion: Altogether, these results suggest that IGF1R may constitute a novel and druggable therapeutic target for the treatment of Cancer in conjunction with chemoimmunotherapies.

Keywords
breast neoplasms; immunotherapy; systems biology.
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