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.