Faculty, Staff and Student Publications

Publication Date

11-1-2024

Journal

Nature

DOI

10.1038/s41586-024-07943-7

PMID

39385035

PMCID

PMC11560846

PubMedCentral® Posted Date

10-9-2024

PubMedCentral® Full Text Version

Post-print

Abstract

For patients with advanced non-small-cell lung cancer (NSCLC), dual immune checkpoint blockade (ICB) with CTLA4 inhibitors and PD-1 or PD-L1 inhibitors (hereafter, PD-(L)1 inhibitors) is associated with higher rates of anti-tumour activity and immune-related toxicities, when compared with treatment with PD-(L)1 inhibitors alone. However, there are currently no validated biomarkers to identify which patients will benefit from dual ICB1,2. Here we show that patients with NSCLC who have mutations in the STK11 and/or KEAP1 tumour suppressor genes derived clinical benefit from dual ICB with the PD-L1 inhibitor durvalumab and the CTLA4 inhibitor tremelimumab, but not from durvalumab alone, when added to chemotherapy in the randomized phase III POSEIDON trial3. Unbiased genetic screens identified loss of both of these tumour suppressor genes as independent drivers of resistance to PD-(L)1 inhibition, and showed that loss of Keap1 was the strongest genomic predictor of dual ICB efficacy-a finding that was confirmed in several mouse models of Kras-driven NSCLC. In both mouse models and patients, KEAP1 and STK11 alterations were associated with an adverse tumour microenvironment, which was characterized by a preponderance of suppressive myeloid cells and the depletion of CD8+ cytotoxic T cells, but relative sparing of CD4+ effector subsets. Dual ICB potently engaged CD4+ effector cells and reprogrammed the tumour myeloid cell compartment towards inducible nitric oxide synthase (iNOS)-expressing tumoricidal phenotypes that-together with CD4+ and CD8+ T cells-contributed to anti-tumour efficacy. These data support the use of chemo-immunotherapy with dual ICB to mitigate resistance to PD-(L)1 inhibition in patients with NSCLC who have STK11 and/or KEAP1 alterations.

Keywords

Animals, Female, Humans, Male, Mice, AMP-Activated Protein Kinase Kinases, Antibodies, Monoclonal, B7-H1 Antigen, Carcinoma, Non-Small-Cell Lung, Clinical Trials, Phase III as Topic, CTLA-4 Antigen, Drug Resistance, Neoplasm, Immune Checkpoint Inhibitors, Kelch-Like ECH-Associated Protein 1, Lung Neoplasms, Mutation, Nitric Oxide Synthase Type II, T-Lymphocytes, Tumor Microenvironment, Tumor Suppressor Proteins, Genes, Tumor Suppressor

Comments

This article has been corrected. See Nature. 2025 Feb 27;639(8054):E19.

Published Open-Access

yes

Additional Files
41586_2025_Article_8767.pdf (624 kB)
Correction
Download

Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.