Deng et al. investigated why NSCLC patients with inactivating LKB1 mutations respond poorly to anti-PD-1 therapy. In non-smokers and GEMM models, loss of LKB1 function was associated with high tumor mutational burden. However, loss of LKB1 also increased autophagic flux and suppressed antigen processing and presentation due to reduced immunoproteasome activity. Autophagy inhibitors targeting the ATG1/ULK1 pathway restored immunoproteasome activity and synergized with anti-PD-1 to enhance CD8+ T cell-dependent tumor regression in Lkb1-mutant mouse models, suggesting a clinical strategy for treating LKB1-mutant NSCLC.
Contributed by Katherine Turner
ABSTRACT: Inactivating mutations in LKB1/STK11 are present in roughly 20% of nonsmall cell lung cancers (NSCLC) and portend poor response to anti-PD-1 immunotherapy. Unexpectedly, we found that LKB1 deficiency correlated with elevated tumor mutational burden (TMB) in NSCLCs from nonsmokers and genetically engineered mouse models, despite the frequent association between high-TMB and anti-PD-1 treatment efficacy. However, LKB1 deficiency also suppressed antigen processing and presentation, which are associated with compromised immunoproteasome activity and increased autophagic flux. Immunoproteasome activity and antigen presentation were restored by inhibiting autophagy through targeting the ATG1/ULK1 pathway. Accordingly, ULK1 inhibition synergized with PD-1 antibody blockade, provoking effector T-cell expansion and tumor regression in Lkb1-mutant tumor models. This study reveals an interplay between the immunoproteasome and autophagic catabolism in antigen processing and immune recognition, and proposes the therapeutic potential of dual ULK1 and PD-1 inhibition in LKB1-mutant NSCLC as a strategy to enhance antigen presentation and to promote antitumor immunity.
Author Info: (1) Division of Hematology & Medical Oncology, Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY,
USA. (2) Lineberger Comprehensive
Author Info: (1) Division of Hematology & Medical Oncology, Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY,
USA. (2) Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA. (3) Laura and Isaac Perlmutter Cancer Center, NYU
Langone Medical Center, New York University, New York, NY, USA. (4) Department of Biochemistry and Molecular Pharmacology, New York University
School of Medicine, New York, NY, USA. (5) Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 6Department
of Radiation Oncology, Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, New York, NY, USA. (7) Center for Cancer
Research, Massachusetts General Hospital, Boston, MA, USA. (8) Department of Medicine, Harvard Medical School, Boston, MA, USA. (9) Department of
Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA. (10) Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical
School, Boston, MA, USA. (11) Department of Medicine, Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, New York, NY,
USA. (12) Department of Pathology, New York University School of Medicine, New York, NY, USA. (13) Department of Medical Oncology, Dana-Farber Cancer
Institute, Harvard Medical School, Boston, MA, USA. (14) Memorial Sloan Kettering Cancer Center, New York, NY, USA. (15) Department of Chemical and
Systems Biology, Chem-H and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, CA, USA. (16) Howard Hughes Medical
Institute, New York University School of Medicine, New York, NY, USA. (17) Departments of Thoracic/Head and Neck Medical Oncology, The University of
Texas MD Anderson Cancer Center, Houston, TX, USA.
