Abstract 4887: DNA repair mutations are associated with mutational burden and T-cell activation signature in lung adenocarcinoma

Abstract

Abstract DNA repair deficiencies have been linked to the generation of immunogenic neo-antigens and increased efficacy of immunotherapies. To determine the impact of mutations in DNA repair genes, specifically those involved in homologous recombination (HR) and mismatch repair (MMR), on infiltrating immune cells in lung adenocarcinoma, we analyzed the expression of “immune metagenes” linked to specific cell types (Angelova et al. 2015) utilizing RNAseq values from TCGA (515 patients, 230 sequenced). Tumors infiltrated by activated CD4 and CD8, all combined T cells, and all combined cell types contained a higher somatic mutation count, while tumors infiltrated by Th17, NK56 bright, and mast cells were linked to lower mutation count (Table 1, * = p<0.05). Patients with high mutational burden displayed a significant increase in infiltrating activated CD4 and CD8, effector memory CD4, all combined T cells, mature dendritic cells, and all combined cell types, as well as significantly increased mutations in HR genes, specifically BRCA2 and PALB2, and MMR genes, specifically MLH1, MSH4, MSH5, EXO1, RFC1, and RFC4. Tumors with HR mutations contained a significant 1.9-fold higher average mutation count with increased infiltrating activated CD4, neutrophils, and NKT cells, as well as decreased activated B cells. Similarly, MMR mutations were associated with a 2.7-fold increase in mutational burden and infiltration by all combined T cells. Further, the degree of alterations in DNA repair genes corresponded to escalating mutational burden, as tumors with 0, 1, or 2-3 mutated HR genes contained an average 188, 330, and 472 mutations, respectively, and those with 0, 1, or 2-3 MMR mutations contained 118, 439, and 639 mutations, respectively. Our characterization revealed significant links between DNA repair deficiencies, mutational burden, and tumor infiltration by activated T cells, thereby identifying potential biomarkers to aid in patient selection for immunotherapy. [J.A. and Y.C. contributed equally to this work.] Association between tumor infiltrating immune cell types and mutational burdenImmune Cell TypeAverage Mutation Count Fold ChangePercent of Patients with Infiltration (%)Effector Memory CD8 T cells2.23.1Memory B cells1.83.3Th1 T cells1.53.1Activated CD4 T cells*1.5*29.7Any immune cell type*1.5*73.0Any T cell*1.5*59.2Activated CD8 T cells*1.4*26.8NK cells1.43.1Effector Memory CD4 T cells1.39.1Dendritic cells1.33.9T gamma-delta cells1.25.6Macrophages1.14.3Mature dendritic cells1.110.9Activated B cells1.18.9Any NK cell1.115.0NK56 dim cells1.09.7Immature B cells0.99.1Plasmacytoid dendritic cells0.93.7Regulatory T cells0.84.1Th17 T cells*0.7*10.3Monocytes0.75.4NKT cells0.73.7NK56 bright cells*0.7*3.9Mast cells*0.6*7.0 Citation Format: Young Kwang Chae, Jonathan F. Anker, Massimo Cristofanilli, Aparna Kalyan, Jason Kaplan, Sunandana Chandra, Benedito Carneiro, Maria Matsangou, Cesar Santa-Maria, Francis Giles. DNA repair mutations are associated with mutational burden and T-cell activation signature in lung adenocarcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4887.