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

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  • dc.contributor.author Alburquerque-Bejar, Juan J.
  • dc.contributor.author Navajas-Chocarro, Pablo
  • dc.contributor.author Saigi, Maria
  • dc.contributor.author Ferrero-Andrés, Ana
  • dc.contributor.author Morillas, Juan M.
  • dc.contributor.author Vilarrubi, Andrea
  • dc.contributor.author Gómez, Antonio
  • dc.contributor.author Mate, José Luís
  • dc.contributor.author Muñoz-Mármol, Ana M.
  • dc.contributor.author Romero, Octavio A.
  • dc.contributor.author Blecua, Pedro
  • dc.contributor.author Davalos, Veronica
  • dc.contributor.author Esteller, Manel
  • dc.contributor.author Pros, Eva
  • dc.contributor.author Llabata, Paula
  • dc.contributor.author Torres-Diz, Manuel
  • dc.contributor.author Esteve-Codina, Anna
  • dc.contributor.author Sánchez Céspedes, Montse
  • dc.date.accessioned 2023-06-15T06:00:22Z
  • dc.date.available 2023-06-15T06:00:22Z
  • dc.date.issued 2023
  • dc.description.abstract 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.
  • dc.description.sponsorship The authors thank Isabel Bartolessis (Cancer Genetics Group) and Eva Mussolen (Cancer Epigenetics Group) at IJC for technical assistance. This work was supported by Spanish grants from the MINECO (PID2020-114541RB-I00 to M.S.-C.) and from the Fundación Científica Asociación Española Contra el Cáncer (GCB14142170MONT to M.S.-C.). P.L. was supported by a fellowship from the Formación de Personal Investigador program (BES-2015-072204) and J.M.M. from the FI program AGAUR (2022 FI_B1 00085M). M.S. was supported by a Juan Rodes contract from the Instituto de Salud Carlos III (JR20/00015). O.A.R. was supported by an AECC contract (INVES19045ROME). We thank the CERCA Program/Generalitat de Catalunya for institutional support.
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Alburquerque-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.2023.101006
  • dc.identifier.doi http://dx.doi.org/10.1016/j.xcrm.2023.101006
  • dc.identifier.issn 2666-3791
  • dc.identifier.uri http://hdl.handle.net/10230/57170
  • dc.language.iso eng
  • dc.publisher Elsevier
  • dc.relation.ispartof Cell Rep Med. 2023 Apr 18;4(4):101006
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-114541RB-I00
  • dc.rights © 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/).
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
  • dc.subject.keyword IFNγ
  • dc.subject.keyword Immunotherapy
  • dc.subject.keyword JAK2
  • dc.subject.keyword MYC
  • dc.subject.keyword PD-L1
  • dc.subject.keyword Lung cancer
  • dc.title MYC activation impairs cell-intrinsic IFNγ signaling and confers resistance to anti-PD1/PD-L1 therapy in lung cancer
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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