Rationale: 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.