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, Pablo; Saigi, Maria; Ferrero-Andrés, Ana; Morillas, Juan M.; Vilarrubi, Andrea; Gómez, Antonio; Mate, José Luís; Muñoz-Mármol, Ana M.; Romero, Octavio A.; Blecua, Pedro; Davalos, Veronica; Esteller, Manel; Pros, Eva; Llabata, Paula; Torres-Diz, Manuel; Esteve-Codina, Anna; Sánchez Céspedes, Montse

doi:http://dx.doi.org/10.1016/j.xcrm.2023.101006

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

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

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.