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Oncoimmunology. 2019 Sep 6;8(11):1657374. doi: 10.1080/2162402X.2019.1657374. eCollection 2019.

Suppression of tumor antigen presentation during aneuploid tumor evolution contributes to immune evasion.

Tripathi R1, Modur V1, Senovilla L2,3, Kroemer G2,3,4,5,6, Komurov K1,7,8,9,10.

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Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Equipe labellisée par la Ligue contre le cancer, Université Paris Descartes, Université Sorbonne Paris Cité, Université Paris Diderot, Université Sorbonne Université, INSERM U1138, Centre de Recherche des Cordeliers, Paris, France.
Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France.
Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
Suzhou Institute for Systems Biology, Chinese Academy of Sciences, Suzhou, China.
Department of Women's and Children's Health, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA.
Oncology Research and Development, Pfizer Inc, Pearl River, NY, USA.


Anti-tumor immune responses impede tumor formation, and cancers have evolved many mechanisms of immune evasion. Confirming earlier findings, we show that human tumors with high chromosomal instability (CIN+) are significantly less immunogenic, as judged by tumor lymphocyte infiltration, compared to those with more stable genomes (CIN-). This finding is paradoxical, as genomic instability is expected to evoke an innate immune response. Importantly, CIN+ tumors and cell lines exhibited suppressed expression of proteins involved in MHC class I antigen presentation at least partly due to DNA hypermethylation of the corresponding genes. Using a mouse model of the in vivo evolution of aneuploid tumors, we found that the induction of chromosomal instability in tumor cells is highly immunogenic due to the activation of the STING/TBK1 pathway and consequent increased interferon signaling and antigen presentation. However, tumors evolving under immune pressure suppress the STING/TBK1 and antigen presentation pathways and evade anti-tumor immune responses. In contrast, CIN+ tumors that develop under low immune pressure in both humans and mice retain efficient MHC class I antigen presentation and immunogenicity. Altogether, this study identifies an important mechanism of immune evasion in chromosomally unstable tumors.


Chromosomal Instability; TCGA; cancer aneuploidy; immunoselection

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