• Warapen Treekitkarnmongkol, Maya Hassane, Ansam Sinjab, Kyle Chang, Kieko Hara, Zahraa Rahal, Jiexin Zhang, Wei Lu, Smruthy Sivakumar, Tina L McDowell, Jacob Kantrowitz, Jianling Zhou, Wenhua Lang, Li Xu, Joshua K Ochieng, Sayuri Nunomura-Nakamura, Shanshan Deng, Carmen Behrens, Maria Gabriela Raso, Junya Fukuoka, Alexandre Reuben, Edwin J Ostrin, Edwin Parra, Luisa M Solis, Avrum E Spira, Florencia McAllister, Tina Cascone, Ignacio I Wistuba, Seyed Javad Moghaddam, Paul A Scheet, Junya Fujimoto, and Humam Kadara.
• Department of Translational Molecular Pathology.
• Am. J. Respir. Crit. Care Med. 2021 Jan 1; 203 (1): 90-101.

AbstractRationale: Early pathogenesis of lung adenocarcinoma (LUAD) remains largely unknown. We found that, relative to wild-type littermates, the innate immunomodulator Lcn2 (lipocalin-2) was increased in normal airways from mice with knockout of the airway lineage gene Gprc5a (Gprc5a-/-) and that are prone to developing inflammation and LUAD. Yet, the role of LCN2 in lung inflammation and LUAD is poorly understood.Objectives: Delineate the role of Lcn2 induction in LUAD pathogenesis.Methods: Normal airway brushings, uninvolved lung tissues, and tumors from Gprc5a-/- mice before and after tobacco carcinogen exposure were analyzed by RNA sequencing. LCN2 mRNA was analyzed in public and in-house data sets of LUAD, lung squamous cancer (LUSC), chronic obstructive pulmonary disease (COPD), and LUAD/LUSC with COPD. LCN2 protein was immunohistochemically analyzed in a tissue microarray of 510 tumors. Temporal lung tumor development, gene expression programs, and host immune responses were compared between Gprc5a-/- and Gprc5a-/-/Lcn2-/- littermates.Measurements and Main Results: Lcn2 was progressively elevated during LUAD development and positively correlated with proinflammatory cytokines and inflammation gene sets. LCN2 was distinctively elevated in human LUADs, but not in LUSCs, relative to normal lungs and was associated with COPD among smokers and patients with LUAD. Relative to Gprc5a-/- mice, Gprc5a-/-/Lcn2-/- littermates exhibited significantly increased lung tumor development concomitant with reduced T-cell abundance (CD4+) and richness, attenuated antitumor immune gene programs, and increased immune cell expression of protumor inflammatory cytokines.Conclusions: Augmented LCN2 expression is a molecular feature of COPD-associated LUAD and counteracts LUAD development in vivo by maintaining antitumor immunity.

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