title: STK11/LKB1 Deficiency Promotes Neutrophil Recruitment and Proinflammatory Cytokine Production to Suppress T-cell Activity in the Lung Tumor Microenvironment.
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.
authors.affiliation: 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.
authors.forename: Shohei
authors.initials: S
authors.lastname: Koyama
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Esra A
authors.initials: EA
authors.lastname: Akbay
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Yvonne Y
authors.initials: YY
authors.lastname: Li
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Amir R
authors.initials: AR
authors.lastname: Aref
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ferdinandos
authors.initials: F
authors.lastname: Skoulidis
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Grit S
authors.initials: GS
authors.lastname: Herter-Sprie
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Buczkowski
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Awad
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Warren L
authors.initials: WL
authors.lastname: Denning
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Lixia
authors.initials: L
authors.lastname: Diao
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Edwin R
authors.initials: ER
authors.lastname: Parra-Cuentas
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
authors.affiliation: University of California, San Francisco, San Francisco, California.
authors.forename: Margaret
authors.initials: M
authors.lastname: Soucheray
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Tran
authors.initials: T
authors.lastname: Thai
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Hajime
authors.initials: H
authors.lastname: Asahina
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kitajima
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Abigail
authors.initials: A
authors.lastname: Altabef
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Jillian D
authors.initials: JD
authors.lastname: Cavanaugh
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Kevin
authors.initials: K
authors.lastname: Rhee
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Peng
authors.initials: P
authors.lastname: Gao
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Haikuo
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Fecci
authors.affiliation: Department of Molecular Pharmacology and Therapeutics, Oncology Research Institute, Loyola University Chicago, Illinois.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shimamura
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Hellmann
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: John V
authors.initials: JV
authors.lastname: Heymach
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: F Stephen
authors.initials: FS
authors.lastname: Hodi
authors.affiliation: 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.
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: David A
authors.initials: DA
authors.lastname: Barbie
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, Massachusetts. kwong1@partners.org peter_hammerman@dfci.harvard.edu glenn.dranoff@novartis.com.
authors.forename: Glenn
authors.initials: G
authors.lastname: Dranoff
authors.affiliation: 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.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Hammerman
authors.affiliation: 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.
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D000818:Animals; D060890:B7-H1 Antigen / Q000032:analysis; D016207:Cytokines / Q000096:biosynthesis*; D006801:Humans; D008175:Lung Neoplasms / Q000276:immunology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D051379:Mice; D009154:Mutation; D020556:Neutrophil Infiltration; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology*; D059016:Tumor Microenvironment
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; D016207:Cytokines; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; C491654:Stk11 protein, mouse; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases
references.citation: Nature. 2014 Nov 27;515(7528):563-7
references.pmid: 25428504
references.citation: Nature. 2012 Mar 29;483(7391):613-7
references.pmid: 22425996
references.citation: Nat Rev Immunol. 2010 Dec;10(12):826-37
references.pmid: 21088683
references.citation: Nature. 2014 Nov 27;515(7528):568-71
references.pmid: 25428505
references.citation: Cancer Discov. 2013 Dec;3(12):1355-63
references.pmid: 24078774
references.citation: Nat Rev Cancer. 2009 Nov;9(11):798-809
references.pmid: 19851315
references.citation: Science. 2015 Apr 3;348(6230):124-8
references.pmid: 25765070
references.citation: J Immunol. 2002 Jul 1;169(1):424-33
references.pmid: 12077273
references.citation: Immunol Rev. 2008 Apr;222:287-98
references.pmid: 18364009
references.citation: Cancer Discov. 2013 Aug;3(8):870-9
references.pmid: 23715154
references.citation: Nature. 2009 Nov 5;462(7269):108-12
references.pmid: 19847166
references.citation: Front Oncol. 2013 Mar 15;3:49
references.pmid: 23508517
references.citation: Nature. 2007 Aug 16;448(7155):807-10
references.pmid: 17676035
references.citation: J Clin Invest. 2014 Dec;124(12):5466-80
references.pmid: 25384214
references.citation: Am J Respir Crit Care Med. 2013 Oct 1;188(7):770-5
references.pmid: 23841470
references.citation: Nature. 2014 Nov 27;515(7528):572-6
references.pmid: 25428506
references.citation: Immunity. 2013 Jul 25;39(1):61-73
references.pmid: 23890064
references.citation: Clin Cancer Res. 2015 Jun 15;21(12):2851-60
references.pmid: 25737507
references.citation: Nature. 2014 Jul 31;511(7511):543-50
references.pmid: 25079552
references.citation: Clin Cancer Res. 2013 Nov 15;19(22):6183-92
references.pmid: 24045185
references.citation: Nature. 2012 Mar 29;483(7391):603-7
references.pmid: 22460905
references.citation: Front Immunol. 2013 Jul 08;4:177
references.pmid: 23847618
references.citation: J Immunol. 2014 Nov 15;193(10):4952-61
references.pmid: 25305322
references.citation: Blood. 2008 Apr 15;111(8):3978-85
references.pmid: 18156493
references.citation: Nature. 2014 Nov 27;515(7528):577-81
references.pmid: 25428507
references.citation: Autoimmun Rev. 2014 Apr-May;13(4-5):496-502
references.pmid: 24424175
references.citation: Cancer Prev Res (Phila). 2011 Jan;4(1):51-64
references.pmid: 21098042
references.citation: N Engl J Med. 2015 May 21;372(21):2018-28
references.pmid: 25891174
references.citation: Cancer Discov. 2014 Apr;4(4):452-65
references.pmid: 24444711
references.citation: Clin Cancer Res. 2014 Oct 1;20(19):5064-74
references.pmid: 24714771
references.citation: Genes Dev. 2007 Jul 15;21(14):1714-9
references.pmid: 17639077
references.citation: Lung Cancer. 2014 Nov;86(2):255-61
references.pmid: 25224251
references.citation: Cancer Discov. 2015 Aug;5(8):860-77
references.pmid: 26069186
references.citation: Eur J Immunol. 2003 Nov;33(11):3117-26
references.pmid: 14579280
references.citation: Breast Cancer Res. 2010;12(5):R80
references.pmid: 20929542
references.citation: Nature. 2009 Nov 5;462(7269):104-7
references.pmid: 19847165
references.citation: Cancer Res. 2014 Sep 1;74(17):4676-84
references.pmid: 25035393