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...

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Detalhes bibliográficos
Autores: Alburquerque-Bejar, Juan J., Navajas-Chocarro, Pablo, Saigi, Maria, Ferrero-Andrés, Ana, Morillas, Juan M., Vilarrubi, Andrea, Gómez, Antonio, Mate, José Luís, Muñoz-Mármol, Ana María, Romero, Octavio A., Blecua, Pedro, Davalos, Veronica, Esteller, Manel, Pros, Eva, Llabata, Paula, Torres-Diz, Manuel, Esteve-Codina, Anna, Sánchez Céspedes, Montse
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Recursos:Universitat Pompeu Fabra
Repositorio:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/57170
Acesso em linha:http://hdl.handle.net/10230/57170
http://dx.doi.org/10.1016/j.xcrm.2023.101006
Access Level:acceso abierto
Palavra-chave:IFNγ
Immunotherapy
JAK2
MYC
PD-L1
Lung cancer
Descrição
Resumo: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.

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