Anoikis-related CTNND1 is associated with immuno-suppressive tumor microenvironment and predicts unfavorable immunotherapeutic outcome in non-small cell lung cancer.

ABSTRACT

Background: Immunotherapy has greatly changed the treatment of advanced non-small cell lung cancer (NSCLC). Anoikis is a programmed cell death process associated with cancer. However, the correlation between anoikis-related genes and the tumor microenvironment (TME) features and immunotherapeutic outcome in NSCLC has not been fully explored. Methods: The bulk and single-cell transcriptome data of NSCLC were downloaded from TCGA and GEO databases. The distribution of anoikis-related genes on different cell types at the single-cell level was analyzed, and these genes specifically expressed by tumor cells and immunotherapy-related were further extracted. Next, the candidate gene CTNND1 was identified and its correlations with the TME features and immunotherapeutic outcome in NSCLC were explored in multiple public cohorts. Finally, an in-house cohort was used to determine the CTNND1 expression and immuno-correlation in NSCLC. Results: At single-cell atlas, we found that anoikis-related genes expressed specifically in tumor cells of NSCLC. By intersecting anoikis-related genes, immunotherapy-associated genes, and the genes expressed in tumor cells, we obtained a special biomarker CTNND1. In addition, cell-cell communication analysis revealed that CTNND1+ tumor cells communicated with immune subpopulations frequently. Moreover, we found that high expression of CTNND1 was related to immuno-suppressive status of NSCLC. The expression of CTNND1 and its immuno-correlation were also validated, and the results showed that CTNND1 was highly expressed in NSCLC tissues and tumors with high CTNND1 expression accompanied with low CD8+ T cells infiltration. Conclusions: Overall, our study reported that CTNND1 can be considered as a novel biomarker for the predication of immunotherapeutic responses and a potential target for NSCLC therapy.