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Cited by 102Cancer Immunotherapy and BiomarkersT-cell and B-cell ImmunologyImmunotherapy and Immune Responses

AXL targeting restores PD-1 blockade sensitivity of STK11/LKB1 mutant NSCLC through expansion of TCF1+ CD8 T cells

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Li, Huiyu, Liu, Zhida, Liu, Longchao, Zhang, Hongyi, Han, Chuanhui, Girard, Luc, Park, Hyunsil, Zhang, Anli +25 more·2022·Cell Reports Medicine
DOI 10.1016/j.xcrm.2022.100554PMC PMC9040166
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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.

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Cited by

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Authors
Li, H., Liu, Z., Liu, L., Zhang, H., Han, C., Girard, L., Park, H., Zhang, A., Dong, C., Ye, J., Rayford, A., Peyton, M., Li, X., Avila, K., Cao, X., Hu, S., Alam, M. M., Akbay, E. A., Solis, L. M., Behrens, C., Hernandez-Ruiz, S., Lu, W., Wistuba, I., Heymach, J. V., Chisamore, M., Micklem, D., Gabra, H., Gausdal, G., Lorens, J. B., Li, B., Fu, Y.-X., Minna, J. D., & Brekken, R. A.
Affiliations
  • The University of Texas Southwestern Medical Center (US)
  • BerGenBio (Norway) (NO)
  • The University of Texas MD Anderson Cancer Center (US)
  • Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
  • University of Bergen (NO)
  • Harold C. Simmons Comprehensive Cancer Center (US)
Corresponding author
  • Liu, Zhida
  • Fu, Yang-Xin
  • Minna, John D.
  • Brekken, Rolf A.
ORCID
Venue
Cell Reports Medicine
Publisher
Elsevier BV
Published
2022-03
Volume
3
Issue
3
Pages
100554
ISSN
2666-3791 (ISSN-L)
DOI
10.1016/j.xcrm.2022.100554
PMC
PMC9040166
OpenAlex
W4220752565
Cited by
102
References
12
Citations by year
2026: 16 · 2025: 31 · 2024: 17 · 2023: 31 · 2022: 7
FWCI
9.00
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports Medicine (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • NORA - Norwegian Open Research Archives (submittedVersion, cc-by-nc-nd)
Funders
  • National Cancer Institute (U54CA210181, P50CA070907, U54CA224065, R01CA243577, P30CA016672, P30CA142543)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01HD087150)
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
non-small cell lung cancer, AXL, anti-PD-1 therapy, immune checkpoint inhibitor resistance, type I interferon, dendritic cells, immunosuppression, bemcentinib, pembrolizumab, combination therapy
MeSH terms
AMP-Activated Protein Kinase Kinases, Axl Receptor Tyrosine Kinase, Animals, Carcinoma, Non-Small-Cell Lung, Humans, Lung Neoplasms, Proto-Oncogene Proteins, Protein Serine-Threonine Kinases, CD8-Positive T-Lymphocytes, Receptor Protein-Tyrosine Kinases, Mice, Programmed Cell Death 1 Receptor

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