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

Alburquerque-Bejar, Juan J.Navajas-Chocarro, PabloSaigi, MariaFerrero-Andrés, AnaMorillas, Juan M.Vilarrubi, AndreaGómez, AntonioMate, José LuísMuñoz-Mármol, Ana M.Romero, Octavio A.Blecua, PedroDavalos, VeronicaEsteller, ManelPros, EvaLlabata, PaulaTorres-Diz, ManuelEsteve-Codina, AnnaSánchez Céspedes, Montse2023-06-152023-06-152023Alburquerque-Bejar JJ, Navajas-Chocarro P, Saigi M, Ferrero-Andres A, Morillas JM, Vilarrubi A, Gomez A, Mate JL, Munoz-Marmol AM, Romero OA, Blecua P, Davalos V, Esteller M, Pros E, Llabata P, Torres-Diz M, Esteve-Codina A, Sanchez-Cespedes M. MYC activation impairs cell-intrinsic IFNγ signaling and confers resistance to anti-PD1/PD-L1 therapy in lung cancer. Cell Rep Med. 2023 Apr 18;4(4):101006. DOI: 10.1016/j.xcrm.2023.1010062666-3791http://hdl.handle.net/10230/57170Elucidating 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.application/pdfeng© 2023 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).MYC activation impairs cell-intrinsic IFNγ signaling and confers resistance to anti-PD1/PD-L1 therapy in lung cancerinfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1016/j.xcrm.2023.101006IFNγImmunotherapyJAK2MYCPD-L1Lung cancerinfo:eu-repo/semantics/openAccess