2026-04-13T18:26:46Zhttps://recercat.cat/oai/request

oai:recercat.cat:2445/2008692025-12-05T12:23:58Zcom_2072_1057col_2072_478916col_2072_478917

00925njm 22002777a 4500 dc Alburquerque Bejar, Juan J. author Navajas Chocarro, Pablo author Saigí, Maria author Ferrero Andrés, Ana author Morillas, Juan M. author Vilarrubi Porta, Andrea author Gomez, Antonio author Mate, José L. author Munoz Marmol, Ana M. author Romero Ferraro, Octavio author Blecua, Pedro author Davalos, Veronica author Esteller, Manel author Pros, Eva author Llabata, Paula author Torres Diz, Manuel author Esteve Codina, Anna author Sánchez Céspedes, Montserrat author 2023-07-19T08:59:52Z 2023-07-19T08:59:52Z 2023-04-01 2023-06-20T15:16:37Z 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-y (IFNy), a cytokine that promotes immunoresponse and modulates programmed death-ligand 1 (PD-L1) levels. We report complete refractoriness to IFNy 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 IFNy-stimulated genes (IySGs) coupled with decreased H3K27ac (histone 3 acetylation at lysine 27) depo-sition and promoter hypermethylation and reduced IFN regulatory factor 1 (IRF1) recruitment to the DNA on IFNy 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 IySGs stimulation by IFNy. 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 IFNy and may predict anti-PD1/L1 efficacy in LC. Càncer de pulmó Immunoteràpia Lung cancer Immunotheraphy MYC activation impairs cell-intrinsic IFNγ signaling and confers resistance to anti-PD1/PD-L1 therapy in lung cancer