Tradeoff between metabolic i-proteasome addiction and immune evasion in triple-negative breast cancer

Abstract

In vitro studies have suggested proteasome inhibitors could be effective in triple-negative breast cancer (TNBC). We found that bortezomib and carfilzomib induce proteotoxic stress and apoptosis via the unfolded protein response (UPR) in TNBC cell lines, with sensitivity correlated with expression of immuno-(PSMB8/9/10) but not constitutive-(PSMB5/6/7) proteasome subunits. Equally, the transcriptomes of i-proteasome–high human TNBCs are enriched with UPR gene sets, and the genomic copy number landscape reflects positive selection pressure favoring i-proteasome activity, but in the setting of adjuvant treatment, this is actually associated with favorable prognosis. Tumor expression of PSMB8 protein (β5i) is associated with levels of MHC-I, interferon-γ–inducible proteasome activator PA28β, and the densities of stromal antigen-presenting cells and lymphocytes (TILs). Crucially, TILs were protective among TNBCs that maintain high β5i but did not stratify survival amongst β5i-low TNBCs. Moreover, β5i expression was lower in brain metastases than in patient-matched primary breast tumors (n = 34; P = 0.007), suggesting that suppression contributes to immune evasion and metastatic progression. Hence, inhibiting proteasome activity could be counterproductive in the adjuvant treatment setting because it potentiates anti-TNBC immunity.

Metaplastic breast cancers frequently express immune checkpoint markers FOXP3 and PD-L1

“…Almost half of the cohort was categorised immune cold (group 1; 49%), which is comparable to a cross-sectional TNBC cohort (53%, ref. 30 ). The MBCs, however, showed a significant reduction in the proportion of group 3 (immune hot) cases compared to TNBC (Fig.…”

Quantitative proteomic analysis of extracellular vesicle subgroups isolated by an optimized method combining polymer‐based precipitation and size exclusion chromatography

“…Interestingly, triple‐negative breast cancer (TNBC) cell lines, including MDA‐MB‐468, are sensitive to proteasome inhibitors (Milacic et al., 2006; Weyburne et al., 2017). High gene expression levels of immunoproteasome complexes ( PSMB8, PSMB9, and PSMB10 ) are related to survival effects in TNBC cell lines (Adwal et al., 2020). The enrichment of this kind of functional modules has been experimentally corroborated in colorectal cancer cells (Choi et al., 2012).…”

Clinicopathologic significance of nuclear HER4 and phospho-YAP(S127) in human breast cancers and matching brain metastases

“… 40 , 45 , 72 It is possible that YAP is expressed at a level that overwhelms 14-3-3-mediated sequestration and/or ubiquitin-mediated proteolysis, particularly for metabolically active tumours that have a high endoplasmic reticulum stress burden. 73 Assuming that serine-127 phosphorylation marks negative feedback on YAP and that its presence in the nucleus is due to ‘overflow’, this implies that YAP inactivation is linked to less aggressive forms of ER+ breast cancer. TNBC aside, our findings in ER+ breast cancer ( Figure 3C ) are consistent with this, and with a recent report identifying YAP as a novel ERα co-factor required for oestrogen-mediated transcriptional regulation of the enhancer landscape in MCF7 cells.…”