Oncotarget

Research Papers:

Mutations in DNA repair genes are associated with increased neo-antigen load and activated T cell infiltration in lung adenocarcinoma

Young Kwang Chae _, Jonathan F. Anker, Preeti Bais, Sandeep Namburi, Francis J. Giles and Jeffrey H. Chuang

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Oncotarget. 2018; 9:7949-7960. https://doi.org/10.18632/oncotarget.23742

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Abstract

Young Kwang Chae1,2,*, Jonathan F. Anker1,*, Preeti Bais3, Sandeep Namburi3, Francis J. Giles1,2 and Jeffrey H. Chuang3,4

1Northwestern University Feinberg School of Medicine, Chicago, 60611, IL, USA

2Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, 60611, IL, USA

3The Jackson Laboratory for Genomic Medicine, Farmington, 06030, CT, USA

4Department of Genetics and Genome Sciences, University of Connecticut Health, Farmington, 06032, CT, USA

*These authors contributed equally to this work

Correspondence to:

Young Kwang Chae, email: young.chae@northwestern.edu

Jeffrey H. Chuang, email: jeff.chuang@jax.org

Keywords: DNA repair; tumor mutational burden; neo-antigens; lung cancer; tumor infiltrating lymphocytes

Received: September 08, 2017 Accepted: October 13, 2017 Published: December 15, 2017

ABSTRACT

Mutations in DNA repair genes lead to increased genomic instability and mutation frequency. These mutations represent potential biomarkers for cancer immunotherapy efficacy, as high tumor mutational burden has been associated with increased neo-antigens and tumor infiltrating lymphocytes. While mismatch repair mutations have successfully predicted response to anti-PD-1 therapy in colorectal and other cancers, they have not yet been tested for lung cancer, and few have investigated genes from other DNA repair pathways. We utilized TCGA samples to comprehensively immunophenotype lung tumors and analyze the links between DNA repair mutations, neo-antigen and total mutational burden, and tumor immune infiltration. Overall, 73% of lung tumors contained infiltration by at least one T cell subset, with high mutational burden tumors containing significantly increased infiltration by activated CD4 and CD8 T cells. Further, mutations in mismatch repair genes, homologous recombination genes, or POLE accurately predicted increased tumor mutational burden, neo-antigen load, and T cell infiltration. Finally, neo-antigen load correlated with expression of M1-polarized macrophage genes, PD-1, PD-L1, IFNγ, GZMB, and FASLG, among other immune-related genes. Overall, after defining the immune infiltrate in lung tumors, we demonstrate the potential value of utilizing gene mutations from multiple DNA repair pathways as biomarkers for lung cancer immunotherapy.


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