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

作者: Shohei Koyama , Esra A. Akbay , Yvonne Y. Li , Amir R. Aref , Ferdinandos Skoulidis

DOI: 10.1158/0008-5472.CAN-15-1439

关键词:

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

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