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-y (IFNy), a cytokine that promotes immunoresponse and modulates progr...

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Hauptverfasser: Alburquerque Bejar, Juan J, Navajas Chocarro, Pablo, Saigí, Maria, Ferrero Andres, Ana, Morillas, Juan M, Vilarrubi, Andrea, Gomez, Antonio, Mate, José L, Munoz Marmol, Ana M, Romero, Octavio A, Blecua, Pedro, Davalos, Veronica, Esteller, Manel, Pros, Eva, Llabata, Paula, Torres Diz, Manuel, Esteve Codina, Anna, Sánchez Céspedes, Montserrat
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Sprache:eng
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Zusammenfassung: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.
ISSN:2666-3791
2666-3791
DOI:10.1016/j.xcrm.2023.101006