Li et al. showed a deficiency of anti-PD-1-sensitive TCF1+CD8+ T cells in KRAS-driven human NSCLC with mutant STK11/LKB1, a tumor suppressor, and in murine lung carcinomas that express, but not in those gene-edited to lack Stk11/Lkb1. Mutant Stk11/Lkb1+ tumors grew faster than edited tumors in immune-competent, but not immune-deficient mice. Inhibiting the innate checkpoint receptor tyrosine kinase Axl with bemcentinib induced IFN-I secretion by DCs, antitumor PD-1+TCF1+CD8+ T cell activity, and anti-PD-1 effects in mouse models. Data from three clinical trial patients supported use of bemcentinib + pembrolizumab for STK11-mutant NSCLC.
Contributed by Paula Hochman
ABSTRACT: Mutations in STK11/LKB1 in non-small cell lung cancer (NSCLC) are associated with poor patient responses to immune checkpoint blockade (ICB), and introduction of a Stk11/Lkb1 (L) mutation into murine lung adenocarcinomas driven by mutant Kras and Trp53 loss (KP) resulted in an ICB refractory syngeneic KPL tumor. Mechanistically this occurred because KPL mutant NSCLCs lacked TCF1-expressing CD8 T cells, a phenotype recapitulated in human STK11/LKB1 mutant NSCLCs. Systemic inhibition of Axl results in increased type I interferon secretion from dendritic cells that expanded tumor-associated TCF1+PD-1+CD8 T cells, restoring therapeutic response to PD-1 ICB in KPL tumors. This was observed in syngeneic immunocompetent mouse models and in humanized mice bearing STK11/LKB1 mutant NSCLC human tumor xenografts. NSCLC-affected individuals with identified STK11/LKB1 mutations receiving bemcentinib and pembrolizumab demonstrated objective clinical response to combination therapy. We conclude that AXL is a critical targetable driver of immune suppression in STK11/LKB1 mutant NSCLC.
Author Info: (1) Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75390-8593, USA (2) Cancer Biology Graduate Program, UT South
Author Info: (1) Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75390-8593, USA (2) Cancer Biology Graduate Program, UT Southwestern Medical Center, Dallas, TX 75390, USA
(3) Department of Pathology, UT Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75390-9072, USA (4) Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center, Dallas, TX 75390, USA (5) BerGenBio ASA, Bergen, Norway (6) Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA (7) Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX 75390, USA (8) Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA (9) Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA (10) Merck & Co., Inc., Kenilworth, NJ 07033, USA (11) Department of Biomedicine, Centre for Cancer Biomarkers, Norwegian Centre of Excellence, University of Bergen, Bergen, Norway (12) Department of Immunology, UT Southwestern Medical Center, Dallas, TX 75390, USA (13) Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA (14) Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA (15) Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA.
