Loss of RBMS1 promotes anti-tumor immunity through enabling PD-L1 checkpoint blockade in triple-negative breast cancer

Abstract

Immunotherapy has been widely utilized in multiple tumors, however, its efficacy in the treatment of triple-negative breast cancers (TNBC) is still being challenged. Meanwhile, functions and mechanisms of RNA binding proteins in regulating immunotherapy for TNBC remain largely elusive. Here we reported that the RNA binding protein RBMS1 is prevalent among immune-cold TNBC. Through a systematic shRNA-mediated screen, we found depletion of RBMS1 significantly reduced the level of programmed death ligand 1 (PD-L1) in TNBC. Clinically, RBMS1 was increased in breast cancer and its level was positively correlated to that of PD-L1. RBMS1 ablation stimulated cytotoxic T cell mediated anti-tumor immunity. Mechanistically, RBMS1 regulated the mRNA stability of B4GALT1, a newly identified glycosyltransferase of PD-L1. Depletion of RBMS1 destabilized the mRNA of B4GALT1, inhibited the glycosylation of PD-L1 and promoted the ubiquitination and subsequent degradation of PD-L1. Importantly, combination of RBMS1 depletion with CTLA4 immune checkpoint blockade or CAR-T treatment enhanced anti-tumor T-cell immunity both in vitro and in vivo. Together, our findings provided a new immunotherapeutic strategy against TNBC by targeting the immunosuppressive RBMS1.

RNF31 represses cell progression and immune evasion via YAP/PD-L1 suppression in triple negative breast Cancer

“…The activation programmed cell death (PD)-1 pathway, which mediates cancer immune evasion, has become an attractive therapeutic target in TNBC [41]. Several studies have shown that the expression level of PD-L1 in TNBC cells correlates with immunotherapy response and overall prognosis [41][42][43]. Interestingly, our RNA sequencing data showed that RNF31 could be a possible inhibition factor for PD-L1 in TNBC.…”

High expression of B4GALT1 is associated with poor prognosis in acute myeloid leukemia

“…The latest study report shows that B4GALT1 is a newly discovered PD-L1 glycosyltransferase, and in triple-negative breast cancer, RBMS1 can bind to the 3′-UTR of B4GALT1 to stabilize its mRNA. Subsequently, highly expressed B4GALT1 can promote PD-L1 glycosylation and increase PD-L1 protein stability, weakening the body's antitumor immune response and promoting tumor immune escape (Zhang et al, 2022). Frontiers in Genetics frontiersin.org However, in LAML, the relationship between B4GALT1 and immune infiltration has not been reported.…”

B7 family protein glycosylation: Promising novel targets in tumor treatment

“…B4GALT1 expression was positively correlated with PD-L1 and CTLA4 expression in bladder cancer ( 93 ). In TNBC, RNA binding motif single strand interacting protein 1 (RBMS1) positively regulates B4GALT1 expression, which is related to the inhibition of inflammation and PD-L1-mediated antitumor immunity ( 94 ). Mechanistically, RBMS1 increases the stability of B4GALT1 mRNA and promotes B4GALT1-mediated PD-L1 galactosylation in N-glycans, thereby reducing PD-L1 protein degradation ( 94 ).…”

“…The glycosylation process mainly involves the sequential action of different glycosyltransferase families, and their expression and function are strictly regulated in each cell ( 100 ). In addition to STT3, B3GNT3, B4GALT1 and α-mannosidase II, which are involved in PD-L1 glycosylation ( 54 , 71 , 94 , 98 ), other glycosyltransferases involved or possibly involved in PD-L1 glycosylation have also been explored. Glycosyltransferase 1 containing domain 1 (GLT1D1) is highly upregulated in incurable B-cell non-Hodgkin’s lymphoma subtypes and early relapsed diffuse large B-cell lymphoma ( 101 ) and may be associated with poor prognosis of colon cancer ( 102 ) and multiple myeloma ( 103 ).…”