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The apoptotic effects of interferon lambdas (IFNλs) have been describedin several types of cancers. However, their effects on human lung cancer cellsand the mechanisms are elusive. In addition, the interaction between IFNλs andother interferons remains unclear. The interplay between IFNα and IFNλ has beenreported. However, although IFNγ is a well-known regulatory interferon, the mechanismsthrough which it regulates IFNλs in lung cancer cells are unknown. These issuesare critical for the application of IFNλs in lung cancer therapy. In this study,we used A549, a cell line derived from a human lung carcinoma, to characterizethe antiproliferative and apoptotic effects of IFNλs on lung cancer, and the interplaybetween IFNγ and IFNλ. Because overexpression of full-length ectopic IFNλR1 ledto cell death, we generated A549 cells stably expressing a chimeric receptor (10R1/λR1),which is composed of the extracellular domain of IL-10 receptor (IL10R1) fusedin tandem to the transmembrane and intracellular domains of the IFNλ receptor(IFNλR1). By comparing with A549 cells stably expressing its cognate vector, wedemonstrated that IL-10 stimulation triggered the intracellular IFNλ signalingvia 10R1/λR1 receptor. By using A549 cells expressing 10R1/λR1, we report thatthe IFNλR1 chain of IFNλ receptor possesses an intrinsic ability to trigger apoptosisin human lung cancer cells. Although it did not suppress cell proliferation, IFNλsignaling via 10R1/λR1 receptor induced cell cycle arrest, externalization ofphosphatidylserine, DNA fragmentation, activation of caspase-3, caspase-8 andcaspase-9. However, the caspase inhibitor Z-VAD-FMK did not prevent apoptosis.In addition, the extent of induced apoptosis correlate with the expression levelsof the IFNλ receptor and the levels of STAT1 activation. Lastly, we demonstratedthat IFNγ sensitized A549 cells to IFNλ-induced apoptosis, via upregulation ofIFNλR1. These data indicate the potential of IFNλ, alone or in combination withIFNγ, in the treatment of human lung carcinoma.

Type III interferon induces apoptosis in human lung cancer cells