Using a genome-wide in vitro screening platform, Zhang et al. identified phospholipase A2 group 10 (PLA2G10) protein as a candidate for T cell exclusion. PLA2G10 is frequently upregulated in human cancers and is associated with T cell exclusion and poor tumor immunity. PLA2G10 overexpression in immunogenic mouse tumors excluded T cells and dampened tumor immunity, resulting in resistance to anti-PD-1 immunotherapy. Mechanistically, PLA2G10 hydrolyzed phospholipids into small lipid metabolites, which inhibited chemokine-mediated T cell mobility. PLA2G10 blockade enhanced T cell infiltration and sensitized PLA2G10-overexpressing tumors to immunotherapy.
Contributed by Shishir Pant
ABSTRACT: T cells are often absent from human cancer tissues during both spontaneously induced immunity and therapeutic immunotherapy, even in the presence of a functional T cell-recruiting chemokine system, suggesting the existence of T cell exclusion mechanisms that impair infiltration. Using a genome-wide in vitro screening platform, we identified a role for phospholipase A2 group 10 (PLA2G10) protein in T cell exclusion. PLA2G10 up-regulation is widespread in human cancers and is associated with poor T cell infiltration in tumor tissues. PLA2G10 overexpression in immunogenic mouse tumors excluded T cells from infiltration, resulting in resistance to anti-PD-1 immunotherapy. PLA2G10 can hydrolyze phospholipids into small lipid metabolites, thus inhibiting chemokine-mediated T cell mobility. Ablation of PLA2G10's enzymatic activity enhanced T cell infiltration and sensitized PLA2G10-overexpressing tumors to immunotherapies. Our study implicates a role for PLA2G10 in T cell exclusion from tumors and suggests a potential target for cancer immunotherapy.
Author Info: (1) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (2) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (3
Author Info: (1) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (2) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (3) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (4) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA. (5) Department of Pathology, Yale University School of Medicine, New Haven, CT, USA. (6) Sciex Demo Lab, Framingham, MA, USA. (7) Sciex Demo Lab, Framingham, MA, USA. (8) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (9) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (10) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (11) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (12) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA. (13) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (14) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (15) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (16) NextCure Inc., Beltsville, MD, USA. (17) NextCure Inc., Beltsville, MD, USA. (18) NextCure Inc., Beltsville, MD, USA. (19) Normunity Inc., Boston, MA, USA. (20) Normunity Inc., Boston, MA, USA. (21) Yale Center for Genome Analysis, Yale University, New Haven, CT, USA. (22) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (23) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (24) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (25) Department of Pathology, Yale University School of Medicine, New Haven, CT, USA. (26) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. Program of Immunology and Immunotherapy, Center for Applied Medical Research, University of Navarra, Pamplona, Spain. (27) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
