Whole-genome doubling drives immune evasion by silencing antigen presentation PMID: 42102810

ADC Targets in Oncology

2026-04-10

Whole-genome doubling drives immune evasion by silencing antigen presentation

Cancer Cell. 2026 May 7:S1535-6108(26)00218-7. doi: 10.1016/j.ccell.2026.04.007.

Pierre Foidart ¹ , Zheqi Li ¹ , Xinran Cai ¹ , Marco Seehawer ¹ , Daniel D Brown ² , Amatullah Tawawalla ³ , Pilar Baldominos ⁴ , Salma Parvin ¹ , Jun Nishida ¹ , Ernesto Rojas-Jimenez ¹ , Triet M Bui ¹ , Benedetto Diciaccio ¹ , Rahul Kumar ⁵ , Brent T Schlegel ⁵ , Marie-Anne Goyette ¹ , TashJae Scales ⁶ , Pengze Yan ¹ , Xintao Qiu ⁶ , Rong Li ⁶ , Yijia Jiang ⁶ , Yingtian Xie ⁶ , Mahmoud Aarabi ⁷ , Xiao-Yun Huang ³ , Laura E Stevens ¹ , Paloma Cejas ⁶ , Lise Mangiante ⁸ , Cristina Irene Sotomayor Vivas ⁸ , Kathleen E Houlahan ⁸ , Christina Curtis ⁸ , Steffi Oesterreich ⁵ , Isaac S Harris ⁹ , Anthony G Letai ¹ , Adrian V Lee ¹⁰ , Henry W Long ⁶ , Judith Agudo ⁴ , Kornelia Polyak ¹¹

Affiliations

1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
2. Institute for Precision Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA.
3. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
4. Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA.
5. Women's Cancer Research Center, UPMC Hillman Cancer Center, Magee-Women's Research Institute, Pittsburgh, PA 15260, USA; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA.
6. Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
7. Departments of Pathology, and Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; UPMC Cytogenetics Laboratoires, UPMC Magee-Womens Hospital, Pittsburgh, PA 15213, USA.
8. Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
9. University of Rochester Medical Center, Rochester, NY 14642, USA.
10. Institute for Precision Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA; Women's Cancer Research Center, UPMC Hillman Cancer Center, Magee-Women's Research Institute, Pittsburgh, PA 15260, USA; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA.
11. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].

Abstract

Whole-genome doubling (WGD) is a common yet poorly understood event associated with poor clinical outcomes. Here, we characterize mechanisms by which WGD drives tumor evolution, utilizing mouse mammary tumor models of WGD established through cell fusion. We find that WGD increases transcriptomic and epigenetic heterogeneity and identify the YM155 BIRC5 inhibitor as a compound specifically suppressing WGD+ tumors. WGD triggers immune evasion by escaping CD8⁺ T cell responses, rendering WGD+ tumors more sensitive to anti-PD-L1. Through single-cell profiling, we discover that WGD+ Cancer cells exhibit reduced antigen presentation and response to IFNγ, attributed to the epigenetic silencing of MHCI transcriptional regulators via elevated histone H3 lysine 27 trimethylation. Further investigations reveal decreased KDM6 activity and increased succinate levels in WGD+ tumors. PRC2 inhibition preferentially suppresses WGD+ tumor growth, enhances antigen presentation, and CD8⁺ T cell infiltration. Our results underscore metabolic and epigenetic alterations as critical drivers of WGD-associated immune escape.

Keywords

antigen presentation; breast cancer; epigenetic silencing; immune escape; whole genome doubling.