Regulation of ferroptosis‐related genes in CD8+ NKT cells and classical monocytes may affect the immunotherapy response after combined treatment in triple negative breast cancer

Abstract

Background

Drug resistance has led to the failure of immunotherapy in triple negative breast cancer patients. Here we aimed to explore the mechanisms of drug resistance in patients in order to enhance their response to immunotherapy.

Methods

We downloaded publicly available single‐cell RNA‐sequencing data of peripheral blood mononuclear cells from patients after treatment to investigate the possible mechanisms of drug resistance. The publicly available TCGA transcriptomic data and somatic mutation data were used for further validation. In this study, a series of bioinformatics and machine learning methods were employed.

Results

We identified the vital roles of CD8+ NKT cells and classical monocytes in the immunotherapy response of triple‐negative breast cancer patients. The proportion of these cell types was significantly increased in group partial response. We also found that downregulation of ferroptosis‐related genes regulates the immune pathway. The analysis of scRNA data and TCGA transcriptomic data presented that DUSP1 may play a crucial role in immunotherapy resistance.

Conclusion

Overall, the composition of the tumor microenvironment affects the immunotherapy response of patients, and DUSP1 may be a potential target for overcoming drug resistance.

Abstract

Combined therapy with atezolizumab and paclitaxel will downregulate the expression of DDIT4 in CD8+ NKT cells and DUSP1 in classical monocytes, which leading to reduced ferroptosis in both cells and consequently inhibited tumor progression.