Abstract
Deficiencies in DNA repair pathways, including mismatch repair (MMR), have been linked to higher tumor mutation burden and improved response to immune checkpoint inhibitors. However, the significance of MMR mutations in lung cancer has not been well characterized, and the relevance of other processes, including homologous recombination (HR) and polymerase epsilon (POLE) activity, remains unclear. Here, we analyzed a dataset of lung squamous cell carcinoma samples from The Cancer Genome Atlas. Variants in DNA repair genes were associated with increased tumor mutation and neoantigen burden, which in turn were linked with greater tumor infiltration by activated T cells. The subset of tumors with DNA repair gene variants but without T cell infiltration exhibited upregulation of TGF-β and Wnt pathway genes, and a combined score incorporating these genes and DNA repair status accurately predicted immune cell infiltration. Finally, high neoantigen burden was positively associated with genes related to cytolytic activity and immune checkpoints. These findings provide evidence that DNA repair pathway defects and immunomodulatory genes together lead to specific immunophenotypes in lung squamous cell carcinoma and could potentially serve as biomarkers for immunotherapy.
Highlights
Immune checkpoint inhibitors have reshaped the landscape of treatment for multiple cancers, including squamous cell carcinoma (SCC) of the lung and other types of non-small cell lung cancer (NSCLC)[1,2]
We hypothesized that a comparable relationship would be elucidated in squamous cell carcinoma (SqCC) of the lung, and that mutations in DNA repair pathways could function as biomarkers predictive of response to immune checkpoint blockade
We evaluated tumors for somatic variants in genes related to mismatch repair (MMR), homologous recombination (HR), or in polymerase epsilon (POLE), and identified changes predicted to be deleterious by the SIFT21 and CADD v1.422 scoring systems
Summary
Immune checkpoint inhibitors have reshaped the landscape of treatment for multiple cancers, including squamous cell carcinoma (SCC) of the lung and other types of non-small cell lung cancer (NSCLC)[1,2]. These treatments inhibit immune regulatory molecules such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed death 1 (PD-1), and programmed death ligand 1 (PD-L1), which normally function to suppress immune cell activity[3,4]. Www.nature.com/scientificreports as in a study of multiple solid tumor types[15] These results have led to the landmark FDA approval for PD-1 inhibitors in MMR-deficient tumors, which represents a paradigm-altering shift towards oncologic treatments centered on molecular profile[15]. We hypothesized that a comparable relationship would be elucidated in squamous cell carcinoma (SqCC) of the lung, and that mutations in DNA repair pathways could function as biomarkers predictive of response to immune checkpoint blockade
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