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. 2017 Dec 15;9(8):7949-7960.
doi: 10.18632/oncotarget.23742. eCollection 2018 Jan 30.

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

Young Kwang Chae #  1   2 , Jonathan F Anker #  1 , Preeti Bais  3 , Sandeep Namburi  3 , Francis J Giles  1   2 , Jeffrey H Chuang  3   4
Affiliations

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

Young Kwang Chae et al. Oncotarget. .

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.

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

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Conflict of interest statement

CONFLICTS OF INTEREST All authors certify that they have no conflicts of interest to disclose.

Figures

Figure 1
Figure 1. Comprehensive immunophenotype of the lung adenocarcinoma microenvironment
(A) Percent of tumors with positive infiltration by each adaptive (black bars) and innate (gray bars) immune cell type, as determined by immune metagene lists and GSEA analysis. Abbreviations: γδ T (TGD) cells, immature DCs (iDCs), myeloid derived suppressor cells (MDSCs), follicular helper T (TFH) cells. (B) Heat map indicating infiltration of immune cell types that either significantly (*P < 0.05) co-occur or are mutually exclusive within tumors.
Figure 2
Figure 2. High mutation burden tumors contain increased TILS, immune infiltration, and a distinct molecular phenotype
(A) Fold change in the percent of patients with adaptive (black bars) and innate (gray bars) immune cell infiltration in those with high compared to low mutation burden, as defined by the median mutation count (excluding cell types with positive tumor infiltration in < 10 samples). Percent of high and low mutational burden tumors classified by (B) oncogene-positivity, (C) cluster type, and (D) histology. * P < 0.05, ** P < 0.01, *** P < 0.001.
Figure 3
Figure 3. DNA repair mutations are biomarkers for total mutational burden and TILs
Total mutation count of tumors with mutations in (A.i) HR genes, (B.i) MMR genes, or (C.i) POLE. Results are presented as mean ± SEM. (A.ii), (B.ii), (C.ii) Percent of DNA repair wildtype (WT; black bars) or mutated (Mut; gray bars) tumors with immune cell infiltration (all immune cell types with P < 0.1 displayed. Red dotted line separates increased and decreased tumor infiltrating immune cell types). * P < 0.05, ** P < 0.01, *** P < 0.001.
Figure 4
Figure 4. DNA repair mutations are biomarkers for high tumor neo-antigen load, which is associated with increased TILs
Neo-antigen count of tumors with (A) HR, (B) MMR, or (C) POLE mutations. Results are presented as mean ± SEM. (D) Percent of neo-antigen low (black bars) or high (gray bars) patients infiltrated by immune cell types (all immune cell types with P < 0.1 displayed). * P < 0.05, ** P < 0.01, *** P < 0.001.
Figure 5
Figure 5. Neo-antigen load correlates with multiple immune-related genes and cytokines, M1-polarized TAMs, PD-L1, PD-1, and favorable OS
(A) Pearson correlation coefficients between neo-antigen count and RNA-seq expression levels of multiple chemokines, immunomodulatory genes, and cytokines (only significantly correlating genes reported). (B) Expression of M1 TAM- and M2 TAM-defining genes in high and low neo-antigen burden tumors (all genes with P < 0.2 displayed). (C) PD-L1 and (D) PD-1 expression in high (top quartile) and low neo-antigen load tumors. Results are presented as mean ± SEM. (E) OS of neo-antigen load high (top quartile) and low tumors. * P < 0.05, ** P < 0.01, *** P < 0.001.
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