TY - JOUR
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
N1 - Publisher Copyright:
© 2016 American Association for Cancer Research.
PY - 2016/3/1
Y1 - 2016/3/1
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84961858396&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84961858396&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-15-1439
DO - 10.1158/0008-5472.CAN-15-1439
M3 - Article
C2 - 26833127
AN - SCOPUS:84961858396
SN - 0008-5472
VL - 76
SP - 999
EP - 1008
JO - Cancer research
JF - Cancer research
IS - 5
ER -