Immunoproteasome Function in Normal and Malignant Hematopoiesis

Abstract

The ubiquitin–proteasome system (UPS) is a central part of protein homeostasis, degrading not only misfolded or oxidized proteins but also proteins with essential functions. The fact that a healthy hematopoietic system relies on the regulation of protein homeostasis and that alterations in the UPS can lead to malignant transformation makes the UPS an attractive therapeutic target for the treatment of hematologic malignancies. Herein, inhibitors of the proteasome, the last and most important component of the UPS enzymatic cascade, have been approved for the treatment of these malignancies. However, their use has been associated with side effects, drug resistance, and relapse. Inhibitors of the immunoproteasome, a proteasomal variant constitutively expressed in the cells of hematopoietic origin, could potentially overcome the encountered problems of non-selective proteasome inhibition. Immunoproteasome inhibitors have demonstrated their efficacy and safety against inflammatory and autoimmune diseases, even though their development for the treatment of hematologic malignancies is still in the early phases. Various immunoproteasome inhibitors have shown promising preliminary results in pre-clinical studies, and one inhibitor is currently being investigated in clinical trials for the treatment of multiple myeloma. Here, we will review data on immunoproteasome function and inhibition in hematopoietic cells and hematologic cancers.

Out of Control: The Role of the Ubiquitin Proteasome System in Skeletal Muscle during Inflammation

“…However, immunoproteasome-specific inhibitors that have been shown to be immunosuppressive in mouse models are in phase I trials and may be clinically approved for treatment of hematopoietic malignancies soon. Their possible benefit in muscle wasting has to be evaluated very carefully in the future [ 370 , 386 ].…”

At the Cutting Edge against Cancer: A Perspective on Immunoproteasome and Immune Checkpoints Modulation as a Potential Therapeutic Intervention

“…On the other hand, other studies suggest that immunoproteasomes affect the quantity rather than the quality of the given generated peptides, influencing also in this case the immune response [ 112 , 118 , 119 ]. Thus, some antigens are exclusively produced by the immunoproteasome or the constitutive proteasome, while others can be processed by both, and some others can be preferentially processed by intermediate-type proteasomes [ 120 , 121 ]. Of note, this distinction between the quantitative and qualitative effects of the antigen repertoire depending on the expression rate of immune–constitutive or mixed proteasome is not simply semantic.…”

“…The tumor microenvironment is profoundly different from that of healthy tissues; this is also due to the presence of tumor-infiltrating lymphocytes (TILs) that release IFNγ and other inflammatory cytokines. Interestingly, immunoproteasome seems to possess both pro- and antitumorigenic properties, which are associated with the modulation of cytokine expression and tumor-associated peptide presentation, respectively [ 121 ].…”

“…Tumor cells can evade recognition by cytotoxic T lymphocytes (CTLs or CD8+ T cells) through downregulation of MHC-I at the cell surface or, additionally, by reducing immunoproteasome subunits expression [ 121 , 169 ] ( Figure 4 ). In fact, non-small-cell lung cancer that undergoes the epithelial–mesenchymal transition shows a reduced immunoproteasome subunits expression: this leads to a dramatic drop of heterogeneity of the antigen/peptide repertoire produced by tumor cells and to poor clinical outcomes [ 170 ].…”

“…Moreover, a polymorphism at amino acid 49 of LMP7 (K49 instead of Q49), localized at the pre-sequence of β5i, reduces the rate of proteasome assembly and is associated with a higher risk of developing colon carcinoma [ 154 ]. On the other hand, overexpression of immunoproteasome subunits due to an increase in IFNγ production by TILs correlates with a better prognosis in different tumors, such as melanoma and breast cancer [ 121 , 168 ].…”