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Cancer Res. 2016 Mar 1;76(5):999-1008. doi: 10.1158/0008-5472.CAN-15-1439. Epub 2016 Feb 1.

STK11/LKB1 Deficiency Promotes Neutrophil Recruitment and Proinflammatory Cytokine Production to Suppress T-cell Activity in the Lung Tumor Microenvironment.

Author information

1
Department of Medical Oncology and Cancer Vaccine Center, Dana Farber Cancer Institute, Boston, Massachusetts. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
2
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts.
3
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
4
Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts.
5
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
6
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
7
University of California, San Francisco, San Francisco, California.
8
Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina.
9
Department of Molecular Pharmacology and Therapeutics, Oncology Research Institute, Loyola University Chicago, Illinois.
10
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
11
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts. kwong1@partners.org peter_hammerman@dfci.harvard.edu glenn.dranoff@novartis.com.
12
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts. kwong1@partners.org peter_hammerman@dfci.harvard.edu glenn.dranoff@novartis.com.
13
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts. Belfer Institute for Applied Cancer Science, Dana Farber Cancer Institute, Boston, Massachusetts. kwong1@partners.org peter_hammerman@dfci.harvard.edu glenn.dranoff@novartis.com.

Abstract

STK11/LKB1 is among the most commonly inactivated tumor suppressors in non-small cell lung cancer (NSCLC), especially in tumors harboring KRAS mutations. Many oncogenes promote immune escape, undermining the effectiveness of immunotherapies, but it is unclear whether the inactivation of tumor suppressor genes, such as STK11/LKB1, exerts similar effects. In this study, we investigated the consequences of STK11/LKB1 loss on the immune microenvironment in a mouse model of KRAS-driven NSCLC. Genetic ablation of STK11/LKB1 resulted in accumulation of neutrophils with T-cell-suppressive effects, along with a corresponding increase in the expression of T-cell exhaustion markers and tumor-promoting cytokines. The number of tumor-infiltrating lymphocytes was also reduced in LKB1-deficient mouse and human tumors. Furthermore, STK11/LKB1-inactivating mutations were associated with reduced expression of PD-1 ligand PD-L1 in mouse and patient tumors as well as in tumor-derived cell lines. Consistent with these results, PD-1-targeting antibodies were ineffective against Lkb1-deficient tumors. In contrast, treating Lkb1-deficient mice with an IL6-neutralizing antibody or a neutrophil-depleting antibody yielded therapeutic benefits associated with reduced neutrophil accumulation and proinflammatory cytokine expression. Our findings illustrate how tumor suppressor mutations can modulate the immune milieu of the tumor microenvironment, and they offer specific implications for addressing STK11/LKB1-mutated tumors with PD-1-targeting antibody therapies.

PMID:
26833127
PMCID:
PMC4775354
[Available on 2017-03-01]
DOI:
10.1158/0008-5472.CAN-15-1439
[Indexed for MEDLINE]
Free PMC Article

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