In B-cell malignancies, genetic changes in the DNA damage response (DDR) pathway commonly cause resistance to chemoimmunotherapy (CIT). Researchers previously demonstrated that CIT synergy depends on secretory interaction between tumor cells and macrophages induced by treatment. For a study, they showed that removing various components of the DDR pathway reduces macrophage phagocytic ability in vitro and in vivo.
In vivo, TP53 deletion impaired phagocytic capability across various B-cell malignancies. Using short conditional RNA sequencing and in vivo cyclophosphamide therapy in the Eμ-TCL1, they showed that loss of macrophage phagocytic capability in Tp53-deleted leukemia is caused by a considerable downregulation of a phagocytic transcriptome signature.
They discovered a TP53-specific increase of proteins associated with extracellular vesicles (EVs) by examining the tumor B-cell proteome. Furthermore, they inhibited EV synthesis in tumor B-cells using CRISPR-knockout (KO) of RAB27A and verified that EVs from TP53-deleted lymphoma cells were responsible for the diminished phagocytic capability in vivo CIT resistance.
Furthermore, they discovered that TP53 deficiency increased both PD-L1 cell surface expression and lymphoma cell EV secretion. Anti-PD-L1 antibodies or PD-L1 CRISPR-KO increased macrophage phagocytic capability and in vivo treatment responsiveness by disrupting EV-bound PD-L1. Thus, they showed that increased EV release and PD-L1 expression are unique pathways of macrophage function change in CIT resistance in TP53-deficient B-cell lymphomas.
