Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells.

Abstract

Recent clinical trials using immunotherapy have demonstrated its potential to control cancer by disinhibiting the immune system. Immune checkpoint blocking (ICB) antibodies against cytotoxic-T-lymphocyte-associated protein 4 or programmed cell death protein 1/programmed death-ligand 1 have displayed durable clinical responses in various cancers. Although these new immunotherapies have had a notable effect on cancer treatment, multiple mechanisms of immune resistance exist in tumours. Among the key mechanisms, myeloid cells have a major role in limiting effective tumour immunity. Growing evidence suggests that high infiltration of immune-suppressive myeloid cells correlates with poor prognosis and ICB resistance. These observations suggest a need for a precision medicine approach in which the design of the immunotherapeutic combination is modified on the basis of the tumour immune landscape to overcome such resistance mechanisms. Here we employ a pre-clinical mouse model system and show that resistance to ICB is directly mediated by the suppressive activity of infiltrating myeloid cells in various tumours. Furthermore, selective pharmacologic targeting of the gamma isoform of phosphoinositide 3-kinase (PI3Kγ), highly expressed in myeloid cells, restores sensitivity to ICB. We demonstrate that targeting PI3Kγ with a selective inhibitor, currently being evaluated in a phase 1 clinical trial (NCT02637531), can reshape the tumour immune microenvironment and promote cytotoxic-T-cell-mediated tumour regression without targeting cancer cells directly. Our results introduce opportunities for new combination strategies using a selective small molecule PI3Kγ inhibitor, such as IPI-549, to overcome resistance to ICB in patients with high levels of suppressive myeloid cell infiltration in tumours.

• Authors: Olivier De Henau, Matthew Rausch, David Winkler, Luis Felipe Campesato, Cailian Liu, Daniel Hirschhorn Cymerman, Sadna Budhu, Arnab Ghosh, Melissa Pink, Jeremy Tchaicha, Mark Douglas, Thomas Tibbitts, Sujata Sharma, Jennifer Proctor, Nicole Kosmider, Kerry White, Howard Stern, John Soglia, Julian Adams, Vito J Palombella, Karen McGovern, Jeffery L Kutok, Jedd D Wolchok, Taha Merghoub
• Journal: Nature (Nature) Vol. 539 Issue 7629 Pg. 443-447 (11 17 2016) ISSN: 1476-4687 [Electronic] England
• PMID: 27828943 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors

Topics

• Animals
• Cell Cycle Checkpoints (drug effects)
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Drug Resistance, Neoplasm (drug effects, immunology)
• Female
• Humans
• Immune Tolerance (drug effects)
• Male
• Melanoma (drug therapy, immunology, pathology)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Myeloid Cells (drug effects, enzymology, immunology)
• Neoplasm Metastasis (drug therapy)
• Phenotype
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• T-Lymphocytes, Cytotoxic (drug effects, immunology)
• Tumor Microenvironment (drug effects, immunology)