STK11/LKB1 deficiency promotes neutrophil recruitment and proinflammatory cytokine production to suppress T-cell activity in the lung tumor microenvironment

Shohei Koyama, Esra A. Akbay, Yvonne Y. Li, Amir R. Aref, Ferdinandos Skoulidis, Grit S. Herter-Sprie, Kevin A. Buczkowski, Yan Liu, Mark M. Awad, Warren L. Denning, Lixia Diao, Jing Wang, Edwin R. Parra-Cuentas, Ignacio I. Wistuba, Margaret Soucheray, Tran Thai, Hajime Asahina, Shunsuke Kitajima, Abigail Altabef, Jillian D. Cavanaugh & 13 others Kevin Rhee, Peng Gao, Haikuo Zhang, Peter E. Fecci, Takeshi Shimamura, Matthew D. Hellmann, John V. Heymach, F. Stephen Hodi, Gordon J. Freeman, David A. Barbie, Glenn Dranoff, Peter S. Hammerman, Kwok Kin Wong

Research output: Contribution to journalArticle

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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 withT-cell-suppressive effects, along with a corresponding increase in the expression of T-cell exhaustion markers and tumorpromoting 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.

Original languageEnglish (US)
Pages (from-to)999-1008
Number of pages10
JournalCancer Research
Volume76
Issue number5
DOIs
StatePublished - Mar 1 2016

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Tumor Microenvironment
Neutrophil Infiltration
Cytokines
T-Lymphocytes
Lung
Neoplasms
Neutrophils
Non-Small Cell Lung Carcinoma
Antibodies
Genetic Suppression
Tumor-Infiltrating Lymphocytes
Mutation
Neutralizing Antibodies
Tumor Cell Line
Tumor Suppressor Genes
Oncogenes
Immunotherapy
Interleukin-6
Ligands
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

STK11/LKB1 deficiency promotes neutrophil recruitment and proinflammatory cytokine production to suppress T-cell activity in the lung tumor microenvironment. / Koyama, Shohei; Akbay, Esra A.; Li, Yvonne Y.; Aref, Amir R.; Skoulidis, Ferdinandos; Herter-Sprie, Grit S.; Buczkowski, Kevin A.; Liu, Yan; Awad, Mark M.; Denning, Warren L.; Diao, Lixia; Wang, Jing; Parra-Cuentas, Edwin R.; Wistuba, Ignacio I.; Soucheray, Margaret; Thai, Tran; Asahina, Hajime; Kitajima, Shunsuke; Altabef, Abigail; Cavanaugh, Jillian D.; Rhee, Kevin; Gao, Peng; Zhang, Haikuo; Fecci, Peter E.; Shimamura, Takeshi; Hellmann, Matthew D.; Heymach, John V.; Hodi, F. Stephen; Freeman, Gordon J.; Barbie, David A.; Dranoff, Glenn; Hammerman, Peter S.; Wong, Kwok Kin.

In: Cancer Research, Vol. 76, No. 5, 01.03.2016, p. 999-1008.

Research output: Contribution to journalArticle

Koyama, S, Akbay, EA, Li, YY, Aref, AR, Skoulidis, F, Herter-Sprie, GS, Buczkowski, KA, Liu, Y, Awad, MM, Denning, WL, Diao, L, Wang, J, Parra-Cuentas, ER, Wistuba, II, Soucheray, M, Thai, T, Asahina, H, Kitajima, S, Altabef, A, Cavanaugh, JD, Rhee, K, Gao, P, Zhang, H, Fecci, PE, Shimamura, T, Hellmann, MD, Heymach, JV, Hodi, FS, Freeman, GJ, Barbie, DA, Dranoff, G, Hammerman, PS & Wong, KK 2016, 'STK11/LKB1 deficiency promotes neutrophil recruitment and proinflammatory cytokine production to suppress T-cell activity in the lung tumor microenvironment', Cancer Research, vol. 76, no. 5, pp. 999-1008. https://doi.org/10.1158/0008-5472.CAN-15-1439
Koyama, Shohei ; Akbay, Esra A. ; Li, Yvonne Y. ; Aref, Amir R. ; Skoulidis, Ferdinandos ; Herter-Sprie, Grit S. ; Buczkowski, Kevin A. ; Liu, Yan ; Awad, Mark M. ; Denning, Warren L. ; Diao, Lixia ; Wang, Jing ; Parra-Cuentas, Edwin R. ; Wistuba, Ignacio I. ; Soucheray, Margaret ; Thai, Tran ; Asahina, Hajime ; Kitajima, Shunsuke ; Altabef, Abigail ; Cavanaugh, Jillian D. ; Rhee, Kevin ; Gao, Peng ; Zhang, Haikuo ; Fecci, Peter E. ; Shimamura, Takeshi ; Hellmann, Matthew D. ; Heymach, John V. ; Hodi, F. Stephen ; Freeman, Gordon J. ; Barbie, David A. ; Dranoff, Glenn ; Hammerman, Peter S. ; Wong, Kwok Kin. / STK11/LKB1 deficiency promotes neutrophil recruitment and proinflammatory cytokine production to suppress T-cell activity in the lung tumor microenvironment. In: Cancer Research. 2016 ; Vol. 76, No. 5. pp. 999-1008.
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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 withT-cell-suppressive effects, along with a corresponding increase in the expression of T-cell exhaustion markers and tumorpromoting 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.",
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T1 - STK11/LKB1 deficiency promotes neutrophil recruitment and proinflammatory cytokine production to suppress T-cell activity in the lung tumor microenvironment

AU - Koyama, Shohei

AU - Akbay, Esra A.

AU - Li, Yvonne Y.

AU - Aref, Amir R.

AU - Skoulidis, Ferdinandos

AU - Herter-Sprie, Grit S.

AU - Buczkowski, Kevin A.

AU - Liu, Yan

AU - Awad, Mark M.

AU - Denning, Warren L.

AU - Diao, Lixia

AU - Wang, Jing

AU - Parra-Cuentas, Edwin R.

AU - Wistuba, Ignacio I.

AU - Soucheray, Margaret

AU - Thai, Tran

AU - Asahina, Hajime

AU - Kitajima, Shunsuke

AU - Altabef, Abigail

AU - Cavanaugh, Jillian D.

AU - Rhee, Kevin

AU - Gao, Peng

AU - Zhang, Haikuo

AU - Fecci, Peter E.

AU - Shimamura, Takeshi

AU - Hellmann, Matthew D.

AU - Heymach, John V.

AU - Hodi, F. Stephen

AU - Freeman, Gordon J.

AU - Barbie, David A.

AU - Dranoff, Glenn

AU - Hammerman, Peter S.

AU - Wong, Kwok Kin

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N2 - 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 withT-cell-suppressive effects, along with a corresponding increase in the expression of T-cell exhaustion markers and tumorpromoting 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.

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