MYC activation impairs cell-intrinsic IFNγ signaling and confers resistance to anti-PD1/PD-L1 therapy in lung cancer

Elucidating the adaptive mechanisms that prevent host immune response in cancer will help predict efficacy of anti-programmed death-1 (PD1)/L1 therapies. Here, we study the cell-intrinsic response of lung cancer (LC) to interferon-γ (IFNγ), a cytokine that promotes immunoresponse and modulates progr...

Full description

Bibliographic Details
Authors: Alburquerque-Béjar, Juan Jos|||0000-0002-9022-124X, Navajas-Chocarro, Pablo, Saigí, Maria|||0000-0001-5815-5388, Ferrero-Andres, Ana, Morillas, Juan M., Vilarrubi, Andrea|||0000-0002-2930-3246, Gómez Moruno, Antonio|||0000-0001-5308-981X, Mate, José L., Munoz-Marmol, Ana M., Romero, Octavio A.|||0000-0003-0229-6530, Blecua, Pedro|||0000-0002-1012-0300, Davalos, Veronica|||0000-0003-4077-5137, Esteller, M.|||0000-0003-4490-6093, Pros, Eva|||0000-0002-2366-7866, Llabata, Paula|||0000-0001-7733-6475, Torres-Diz, Manuel, Esteve-Codina, Anna|||0000-0003-0361-2873, Sánchez Céspedes, Montse|||0000-0002-6045-5627
Format: article
Publication Date:2023
Country:España
Institution:Universitat Autònoma de Barcelona
Repository:Dipòsit Digital de Documents de la UAB
Language:English
OAI Identifier:oai:ddd.uab.cat:289528
Online Access:https://ddd.uab.cat/record/289528
https://dx.doi.org/urn:doi:10.1016/j.xcrm.2023.101006
Access Level:Open access
Description
Summary:Elucidating the adaptive mechanisms that prevent host immune response in cancer will help predict efficacy of anti-programmed death-1 (PD1)/L1 therapies. Here, we study the cell-intrinsic response of lung cancer (LC) to interferon-γ (IFNγ), a cytokine that promotes immunoresponse and modulates programmed death-ligand 1 (PD-L1) levels. We report complete refractoriness to IFNγ in a subset of LCs as a result of JAK2 or IFNGR1 inactivation. A submaximal response affects another subset that shows constitutive low levels of IFNγ-stimulated genes (IγSGs) coupled with decreased H3K27ac (histone 3 acetylation at lysine 27) deposition and promoter hypermethylation and reduced IFN regulatory factor 1 (IRF1) recruitment to the DNA on IFNγ stimulation. Most of these are neuroendocrine small cell LCs (SCLCs) with oncogenic MYC/MYCL1/MYCN. The oncogenic activation of MYC in SCLC cells downregulates JAK2 and impairs IγSGs stimulation by IFNγ. MYC amplification tends to associate with a worse response to anti-PD1/L1 therapies. Hence alterations affecting the JAK/STAT pathway and MYC activation prevent stimulation by IFNγ and may predict anti-PD1/L1 efficacy in LC.

Similar Items