Overcoming Resistance to Checkpoint Blockade Therapy by Targeting PI3K-γ in Myeloid Cells

By Olivier de Henau, M. Rausch, D. Winkler, L. Campesato, Cailian Liu, D. H. Cymerman, S. Budhu, Arnab Ghosh, M. Pink, J. Tchaicha and 14 more. Nature, 2016

786 citations recorded by the source corpus.

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.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/29ba8e1d2eed039a27636f9a572e865c65d134df

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In Immunology

1. Di Zhao
2. Lewis C. Cantley
3. D. Spring
4. Guocan Wang
5. R. DePinho

In Oncology

1. Lewis C. Cantley
2. R. Abraham
3. R. DePinho

Citations in the corpus

• CCRK is a novel signalling hub exploitable in cancer immunotherapy (2018, result): “Importantly, knockout of Ccrk further enhanced the therapeutic efficacy of immune checkpoint PD-L1 blockade therapy in a HCC orthotopic mouse model, which is consistent with the role of MDSCs in checkpoint therapy resistance (De Henau et al., 2016; Sade-Feldman et al., 2016).”
• The PI3K pathway in human disease (2017, background): “Instead, exciting evidence that p110g inhibitors can reprogram the immune milieu in tumors (discussed below) has led to clinical trials in cancer of a selective p110g inhibitor (IPI549) combined with immunotherapy (De Henau et al., 2016).”
• Genetics and biology of prostate cancer (2018, background): “…can potentiate the efficacy of various immunotherapies, including im- mune checkpoint inhibitors (Highfill et al. 2014; Motoshima et al. 2015; De Henau et al. 2016; Clavijo et al. 2017; Foubert et al. 2017; Lu et al. 2017a; Orillion et al. 2017), adoptive T-cell therapy (Kodumudi et al.…”