LRRC3B and its promoter hypomethylation status predicts response to anti-PD-1 based immunotherapy

Abstract

Background: The leucine rich repeat containing 3B (LRRC3B) gene is a tumor suppressor gene involved in the anti-tumor immune microenvironment. Expression of LRRC3B and DNA methylation at the LRRC3B promoter region may serve as a useful marker to predict response to anti-PD-1 therapy. However, no studies have yet systematically explored the protective role of LRRC3B methylation in tumor progression and immunity.

Methods: Expression of LRRC3B of 33 cancer types in The Cancer Genome Atlas (TCGA) was downloaded from UCSC Xena (http://xena.ucsc.edu/). And, we evaluated the differential expression of LRRC3B according to tumor stage, overall survival, and characteristics of the tumor microenvironment. The immunotherapeutic cohorts included IMvigor21, GSE119144, and GSE72308 which were obtained from the Gene Expression Omnibus database. We conducted pearson correlation analysis of LRRC3B and tumor microenvironment (TME) in pan-cancer. Also, six immune cell types (B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells) and tumor purity were analyzed using the Tumor IMmune Estimation Resource (TIMER1.0) (Tumor IMmune Estimation Resource (TIMER2.0). And, a "silencing score" model base on LRRC3B promoter methylation to predict overall survival (OS) by multivariate Cox regression analysis was constructed. Finally, the model was applied to predict anti-PD-1 therapy in non-small cell lung cancer (NSCLC) and breast cancer (BRCA).

Results: LRRC3B expression associated with less tumor invasion, less severe tumor stage, and decreased metastasis. The inactivation of LRRC3B promoted the enrichment of immuneosuppressive cells, including myeloid-derived suppressor cells (MDSCs), cancer-associated fibroblasts (CAFs), M2 subtype of tumor-associated macrophages (M2-TAMs), M1 subtype of tumor-associated macrophages (M1-TAMs), and regulatory T (Treg) cells. A high silencing score was significantly associated with immune inhibition, low expression of LRRC3B, poor patient survival, and activation of cancer-related pathways.

Conclusion: Our comprehensive analysis demonstrated the potential role of LRRC3B in the anti-tumor microenvironment, clinicopathological features of cancer, and disease prognosis. It suggested that LRRC3B methylation could be used as a powerful biomarker to predict immunotherapy responses in NSCLC and BRCA.

Keywords: DNA methylation; immunotherapy; leucine rich repeat containing 3B; pan-cancer; tumor immune microenvironment.