Tetrathiomolybdate (TM)-associated copper depletion influences collagen remodeling and immune response in the pre-metastatic niche of breast cancer

Abstract

Tetrathiomolybdate (TM) is a novel, copper-depleting compound associated with promising survival in a phase II study of patients with high-risk and triple-negative breast cancer. We sought to elucidate the mechanism of TM by exploring its effects on collagen processing and immune function in the tumor microenvironment (TME). Using an exploratory cohort, we identified markers of collagen processing (LOXL2, PRO-C3, C6M, and C1M) that differed between those with breast cancer versus controls. We measured these collagen biomarkers in TM-treated patients on the phase II study and detected evidence of decreased collagen cross-linking and increased degradation over formation in those without disease compared to those who experienced disease progression. Preclinical studies revealed decreased collagen deposition, lower levels of myeloid-derived suppressor cells, and higher CD4+ T-cell infiltration in TM-treated mice compared with controls. This study reveals novel mechanisms of TM targeting the TME and immune response with potential applications across cancer types.

Cuproptosis scoring system to predict the clinical outcome and immune response in bladder cancer

“…Further, this study identified seven genes (FDX1, LIAS, LIPT1, DLD, DLAT, PDHA1, and PDHB) that promote cuproptosis, as well as three genes (MTF1, GLS, and CDKN2A) that inhibit it. In previous studies, it was found that the copper depletion caused by tetrathiomolybdate (TM) influences immune response, and intratumoral copper ions may be able to regulate PD-L1 expression and influence tumor immune escape ( 9 , 10 ). Consistently, the latest report of Bian et al also showed that cuproptosis was significantly correlated with immune cell infiltration and PD-1 expression in clear cell renal cell carcinoma (ccRCC) ( 11 ).…”

Comprehensive investigation into cuproptosis in the characterization of clinical features, molecular characteristics, and immune situations of clear cell renal cell carcinoma

“…Zheng et al found that when using the disulfiram/copper codelivery system to treat glioblastoma, the efficacy was reinforced via its remodeling effect on the immune microenvironment of the glioma (28). Liu and colleagues reported that tetrathiomolybdate (TM), a promising anticancer compound, influenced collagen remodeling and enhanced immune response by depleting intracellular copper in breast cancer (29). Yet, rare studies introduced the immune correlation in copper-induced cell death.…”

Relationship between copper and immunity: The potential role of copper in tumor immunity

“…Some studies have reported on the relationship between copper and tumor immunity, such as the reduction of copper in mouse mesothelioma associated with CD4+ T cell infiltration ( 103 ), the effect of anti-tumor drug Dp44mT on T cell activity through a copper-related mechanism ( 104 , 105 ), the apoptosis of bone marrow-derived suppressor cells (MDSCs) and the enhancement of anti-tumor immune responses through selective copper chelation in a drug-resistant tumor model ( 106 ) and the downregulation of ACO3 (copper-containing amine oxidase) in lung cancer leading to reduced adherent aggregation of CD4+ cells ( 107 ). In a phase II study of high-risk and triple-negative patients with breast cancer, tetrathiomolybdate (TTM) reduced collagen deposition, decreased MDSCs levels and increased CD4+ T cell infiltration in the treated mice ( 108 ). In 2020, Voli ( 40 ) was the first to propose that copper ions could regulate the expression of the immune checkpoint PD-L1, opening up the possibility and potential of copper ions to participate in tumor therapy by interfering with tumor immunity.…”