Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells.
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.
Memorial Sloan Kettering Cancer Center, Parker Institute for Cancer Immunotherapy and Swim Across America/Ludwig Collaborative Laboratory, New York, New York 10065, USA.
Olivier
O
De Henau
Infinity Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA.
Matthew
M
Rausch
Infinity Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA.
David
D
Winkler
Memorial Sloan Kettering Cancer Center, Parker Institute for Cancer Immunotherapy and Swim Across America/Ludwig Collaborative Laboratory, New York, New York 10065, USA.
Luis Felipe
LF
Campesato
Memorial Sloan Kettering Cancer Center, Parker Institute for Cancer Immunotherapy and Swim Across America/Ludwig Collaborative Laboratory, New York, New York 10065, USA.
Cailian
C
Liu
Memorial Sloan Kettering Cancer Center, Parker Institute for Cancer Immunotherapy and Swim Across America/Ludwig Collaborative Laboratory, New York, New York 10065, USA.
Daniel Hirschhorn
DH
Cymerman
Memorial Sloan Kettering Cancer Center, Parker Institute for Cancer Immunotherapy and Swim Across America/Ludwig Collaborative Laboratory, New York, New York 10065, USA.
Sadna
S
Budhu
Memorial Sloan Kettering Cancer Center, Parker Institute for Cancer Immunotherapy and Swim Across America/Ludwig Collaborative Laboratory, New York, New York 10065, USA.
Arnab
A
Ghosh
Infinity Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA.
Melissa
M
Pink
Infinity Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA.
Jeremy
J
Tchaicha
Infinity Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA.
Mark
M
Douglas
Infinity Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA.
Thomas
T
Tibbitts
Infinity Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA.
Sujata
S
Sharma
Infinity Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA.
Jennifer
J
Proctor
Infinity Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA.
Nicole
N
Kosmider
Infinity Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA.
Kerry
K
White
Infinity Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA.
Howard
H
Stern
Infinity Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA.
John
J
Soglia
Infinity Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA.
Julian
J
Adams
Infinity Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA.
Vito J
VJ
Palombella
Infinity Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA.
Karen
K
McGovern
Infinity Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA.
Jeffery L
JL
Kutok
Memorial Sloan Kettering Cancer Center, Parker Institute for Cancer Immunotherapy and Swim Across America/Ludwig Collaborative Laboratory, New York, New York 10065, USA.|Weill Cornell Medical and Graduate Schools, New York, New York 10065, USA.
Jedd D
JD
Wolchok
Memorial Sloan Kettering Cancer Center, Parker Institute for Cancer Immunotherapy and Swim Across America/Ludwig Collaborative Laboratory, New York, New York 10065, USA.
Taha
T
Merghoub
D000818:Animals; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000276:immunology; D005260:Female; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology*; D009362:Neoplasm Metastasis / Q000188:drug therapy; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology
D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors