title: TAM receptor tyrosine kinases as emerging targets of innate immune checkpoint blockade for cancer therapy.
abstract: Cancer immunotherapy utilizing T-cell checkpoint inhibitors has shown tremendous clinical success. Yet, this mode of treatment is effective in only a subset of patients. Unresponsive patients tend to have non-T-cell-inflamed tumors that lack markers associated with the activation of adaptive anti-tumor immune responses. Notably, elimination of cancer cells by T cells is critically dependent on the optimal activity of innate immune cells. Therefore, identifying new targets that regulate innate immune cell function and promote the engagement of adaptive tumoricidal responses is likely to lead to the development of improved therapies against cancer. Here, we review the TAM receptor tyrosine kinases-TYRO3, AXL, and MERTK-as an emerging class of innate immune checkpoints that participate in key steps of anti-tumoral immunity. Namely, TAM-mediated efferocytosis, negative regulation of dendritic cell activity, and dysregulated production of chemokines collectively favor the escape of malignant cells. Hence, disabling TAM signaling may promote engagement of adaptive immunity and complement T-cell checkpoint blockade.
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Yemsratch T
authors.initials: YT
authors.lastname: Akalu
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.|Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Carla V
authors.initials: CV
authors.lastname: Rothlin
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA.|Department of Neurology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Sourav
authors.initials: S
authors.lastname: Ghosh
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061025:Costimulatory and Inhibitory T-Cell Receptors / Q000276:immunology; D004359:Drug Therapy, Combination; D006801:Humans; D007113:Immunity, Innate; D007167:Immunotherapy / Q000379:methods*; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D011518:Proto-Oncogene Proteins / Q000276:immunology / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D019139:Tumor Escape; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D000911:Antibodies, Monoclonal; D061025:Costimulatory and Inhibitory T-Cell Receptors; D011518:Proto-Oncogene Proteins; C097072:MERTK protein, human; D020794:Receptor Protein-Tyrosine Kinases; C084944:TYRO3 protein, human; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase; C000722289:AXL protein, human
keywords: 
  AXL
  ; 
  MERTK
  ; TYRO3; innate immune checkpoints