ULK1 Inhibition Restores Antigen Presentation in LKB1-Mutant Lung Cancer

Mutations in LKB1 (also known as STK11) are associated with poor prognosis in non–small cell lung cancer (NSCLC), and despite the fact that LKB1-mutant NSCLCs often exhibit high tumor mutation burden (TMB)—which often portends favorable responses to PD-1 blockade—these cancers have poor response rates to immune checkpoint blockade. Deng and colleagues confirmed that lack of LKB1 in cell lines, genetically engineered mouse models, and patients was correlated with high TMB, finding through in vitro experiments that LKB1 loss caused defects in DNA double-strand break repair via homologous recombination. Importantly, LKB1 loss caused defective antigen presentation resulting from decreased expression of components of the immunoproteasome, a specialized proteasome that generates immunogenic peptides for presentation by MHC-I, and this reduced antigen presentation could facilitate immune evasion by LKB1-mutant tumors. Deeper investigation revealed that immunoproteasome activity and antigen presentation in LKB1-mutant cancer cells could be restored via pharmacologic inhibition of the autophagy regulator ULK1, a serine/threonine kinase. Further, in vivo, ULK1 inhibition led to increased immunoproteasome activity, greater lung tumor infiltration by CD4⁺ and CD8⁺ T cells, and—although pharmacologic inhibition of ULK1 had no antitumor activity on its own—enhanced response to treatment with anti–PD-1. Mechanistically, tumor-intrinsic effects were found not to underlie the improved response of ULK1 inhibitor–treated LKB1-mutant lung tumors to anti–PD-1; rather, this effect depended on the activity of cytotoxic CD8⁺ T cells. Collectively, these findings reveal a reason for the otherwise counterintuitive resistance of LKB1-mutant NSCLCs to immune checkpoint blockade and suggest that targeting ULK1 may enhance anti–PD-1 efficacy against these tumors.

Deng J, Thennavan A, Dolgalev I, Chen T, Li  J, Marzio A, et al. ULK1 inhibition overcomes compromised antigen presentation and restores antitumor immunity in LKB1-mutant lung cancer. Nat Cancer 2021;2:503–14.

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