Augmented Lipocalin-2 Is Associated with Chronic Obstructive Pulmonary Disease and Counteracts Lung Adenocarcinoma Development

Abstract

<b>Rationale:</b> Early pathogenesis of lung adenocarcinoma (LUAD) remains largely unknown. We found that, relative to wild-type littermates, the innate immunomodulator <i>Lcn2</i> (lipocalin-2) was increased in normal airways from mice with knockout of the airway lineage gene <i>Gprc5a</i> (<i>Gprc5a</i>^-/-) and that are prone to developing inflammation and LUAD. Yet, the role of LCN2 in lung inflammation and LUAD is poorly understood.<b>Objectives:</b> Delineate the role of <i>Lcn2</i> induction in LUAD pathogenesis.<b>Methods:</b> Normal airway brushings, uninvolved lung tissues, and tumors from <i>Gprc5a</i>^-/- mice before and after tobacco carcinogen exposure were analyzed by RNA sequencing. <i>LCN2</i> 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 <i>Gprc5a</i>^-/- and <i>Gprc5a</i>^-/-/<i>Lcn2</i>^-/- littermates.<b>Measurements and Main Results:</b><i>Lcn2</i> was progressively elevated during LUAD development and positively correlated with proinflammatory cytokines and inflammation gene sets. <i>LCN2</i> 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 <i>Gprc5a</i>^-/- mice, <i>Gprc5a</i>^-/-/<i>Lcn2</i>^-/- 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.<b>Conclusions:</b> Augmented LCN2 expression is a molecular feature of COPD-associated LUAD and counteracts LUAD development <i>in vivo</i> by maintaining antitumor immunity.