Abstract

Lung cancer is one of the most common and mortal malignancies, usually with a poor prognosis in its advanced or recurrent stages. Recently, immune checkpoint inhibitors (ICIs) immunotherapy has revolutionized the treatment of human cancers including lung adenocarcinoma (LUAD), and significantly improved patients’ prognoses. However, the prognostic and predictive outcomes differ because of tumor heterogeneity. Here, we present an effective method, GDPLichi (Genes of DNA damage repair to predict LUAD immune checkpoint inhibitors response), as the signature to predict the LUAD patient’s response to the ICIs. GDPLichi utilized only 7 maker genes from 8 DDR pathways to construct the predictive model and classified LUAD patients into two subgroups: low- and high-risk groups. The high-risk group was featured by worse prognosis and decreased B cells, CD8+ T cells, CD8+ central memory T cells, hematopoietic stem cells (HSC), myeloid dendritic cells (MDC), and immune scores as compared to the low-risk group. However, our research also suggests that the high-risk group was more sensitive to ICIs, which might be explained by increased TMB, neoantigen, immune checkpoint molecules, and immune suppression genes’ expression, but lower TIDE score as compared to the low-risk group. This conclusion was verified in three other LUAD cohort datasets (GSE30219, GSE31210, GSE50081).

Highlights

  • Lung cancer ranks the second in incidence and top in mortality among malignancies worldwide [1], of which lung adenocarcinoma is the most common subtype [2]

  • Based on the expressions and weights calculated by Cox regression on these genes, we developed a classifier, GDPLichi (Genes of DDR to Predict lung adenocarcinoma (LUAD) immune checkpoint inhibitors), as the signature to predict the ICIs response

  • Our results showed that the immune scores, B cells, hematopoietic stem cells (HSC), myeloid dendritic cells (MDC), CD8+ T cells, and CD8+ central memory T cells were significantly higher in low-risk groups compared to high-risk groups, suggesting a higher tumor-infiltrating lymphocyte (TIL) in the low-risk group (Figures 5A–F)

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Summary

INTRODUCTION

Lung cancer ranks the second in incidence and top in mortality among malignancies worldwide [1], of which lung adenocarcinoma is the most common subtype [2]. Recent studies have reported that tumor mutation burden (TMB) is closely related to the efficacy of ICIs response [11, 12] and can be used as a predictive marker for the efficacy of ICI treatment. TIDE uses a specific set of marker genes to estimate dysfunction of tumor-infiltrating cytotoxic T lymphocyte and exclusion of CTL by an immunosuppressive factor to predict patients’ response to ICIs. Patients with lower TIDE scores have a lower chance of antitumor immune escape, having a higher response rate of ICIs treatment [22]. Based on the expressions and weights calculated by Cox regression on these genes, we developed a classifier, GDPLichi (Genes of DDR to Predict LUAD immune checkpoint inhibitors), as the signature to predict the ICIs response. The highrisk subgroup had a worse prognosis but is presumably more efficacious towards ICIs treatment

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