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

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.

Targeted deep sequencing from multiple sources demonstrates increased NOTCH1 alterations in lung cancer patient plasma

“…34,50,51 Some mutations in mismatch repair genes, homologous recombination genes, or POLE have been associated with high mutation load. 30,52 As previously reported, we found that mutation load varied among lung cancer patients and we identified six genes that could significantly affect patient mutation load 34 ( Figure 2D-E). Interestingly NOTCH1 was significantly associated with mutational burden, as was MET, KDR, BRAF, APC and KAS, yet no association was observed with TP53 or EGFR.…”

Patient Selection for Anti-PD-1/PD-L1 Therapy in Advanced Non-Small-Cell Lung Cancer: Implications for Clinical Practice

“…In a recent analysis from 15,529 lung cancer tumors, only 0.3% were MSI-high and 1.0% had mutations in DNA repair genes (MLH1, MSH2, POLE); the presence of either correlated with a high TMB (p < 0.0001) [85]. A link between DNA repair deficiencies, TMB, neoantigen load and tumor-infiltrating lymphocytes has been demonstrated in lung adenocarcinoma [101], but further study is required to correlate this with ICI efficacy.…”

Pan-cancer identification of clinically relevant genomic subtypes using outcome-weighted integrative clustering

“…In addition to the hypermutated subtypes of endometrial, bladder and colorectal cancers, we also observed high TMB subgroups with concurrently high expression of CD8 T-cell markers in cervical cancer c1 subtype ( Supplementary Fig 4a and 5a ), head and neck cancer c4 subtype (Supplementary Fig 4c, 5c) , lung adenocarcinoma c3 subtype ( Supplementary Fig 4f and 5f ), lung squamous cell carcinoma c4 subtype ( Supplementary Fig 4g and 5g ) and stomach cancer c1 subtype ( Supplementary Fig 4h and 5h ). There are prior observations that high mutational burden is associated with increased neo-antigen load and activated T-cell infiltration in lung cancer 20 . Our analysis revealed that such association may be more widely present in multiple cancer types.…”