Abstract 1355: Functional inactivation of LKB1 increases the production of pro-inflammatory cytokines and governs response to immune modulation

Abstract

Abstract LKB1/STK11 is one of the most commonly mutated tumor suppressors in non-small cell lung cancers. Inactivation of LKB1/STK11 is common in lung cancers with mutated KRAS alleles (1) and results in a clinically more aggressive and metastatic phenotype (2-5). Here, we show in genetically engineered mouse models (GEMMs) and in primary human cancer specimens that loss of LKB1/STK11 in the context of mutated KRAS has a marked effect on the tumor immune microenvironment characterized by accumulation of neutrophils and of tumor promoting cytokines including interleukin (IL)-6. Importantly, Kras/Lkb1 tumors also carry reduced number of tumor-infiltrating lymphocytes with the infiltrating lymphocytes expressing higher levels of T cell exhaustion markers and greater proportions of regulatory T cells as compared to KRAS-driven (Kras) tumors. We also found that presence of LKB1 mutation was negatively correlated with programmed death-1 ligand-1 (PD-L1) expression in mouse and human lung tumors and that antibodies therapeutically targeting this immune checkpoint were ineffective in Kras/Lkb1 mice. In contrast, an IL-6 neutralizing antibody showed clinical benefit in the Kras/Lkb1 model via the reduction of neutrophil accumulation and proinflammatory cytokines. These findings suggest that LKB1 loss of function exacerbates the tumor inflammatory microenvironment in lung cancers and that targeting the aberrant cytokine signaling in LKB1-deficient tumors could be a viable therapeutic option. Citation Format: Esra A. Akbay, Shohei Koyama, Yvonne Li, Grit S. Herter-Sprie, Tran C. Thai, Amir R. Aref, Margaret Soucheray, Takeshi Shimamura, David A. Barbie, Glenn Dranoff, Peter S. Hammerman, Kwok-Kin Wong. Functional inactivation of LKB1 increases the production of pro-inflammatory cytokines and governs response to immune modulation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1355. doi:10.1158/1538-7445.AM2015-1355