From oncogenesis to prognosis: the roles of the immunoproteasome in cancer

Abstract

The proteasome (prosome, macropain) is a key cellular organelle responsible primarily for protein homeostasis, by degrading damaged or misfolded proteins. Proteasome-processed protein fragments can then be further trimmed and funneled to the major histocompatibility complex class I (MHC-I) antigen presentation pathway for cell surface display and immune recognition. Various types of proteasomes can be found in mammalian cells with different expression patterns and cleavage abilities. As such, the immunoproteasome (ImP) preferentially cleaves proteins to yield MHC-I-compatible fragments. It is constitutively expressed by some immune cells and can be induced by pro-inflammatory signals. Interestingly, it was also found to be expressed in multiple types of cancers and proteasome activity can be modulated by some cancer therapies. A better understanding of its impact on cancer progression, prognosis and treatment response is therefore needed to guide treatment decisions. In this review, we focus on the multiple roles of the ImP in cancer, including its interplay with the immune system, as well as its impact on patient outcomes.

Keywords: anti-tumor immunity; cancer; clinical outcome; immunoproteasome; oncogenesis.

Figure 1

Schematic representation of the roles of the ImP across different stages of cancer progression. Most cancers exhibit increased ImP expression compared to healthy tissues while some others repress ImP expression. The known mechanisms by which cancers regulate ImP expression are depicted. The effects of the ImP in oncogenesis, anti-tumor immunity and outcomes are also outlined.

Figure 2

Schematic representation of the regulation of ImP subunit expression. The ImP subunits can be induced via PU.1, STAT1/IRF1, NF-κB, AP1 or CREB. The figure illustrates various stimuli that trigger the expression of PSMB8, 9 and/or 10.

Figure 3

Schematic representation of the functional outcomes of ImP activity in normal immune function, tumor-promotion and tumor-suppression. The roles of the ImP in normal immune functions includes increased MHC-I presentation, immunopeptidome diversification, T cell activation, increased differentiation of CD4+ T cells into Th1 or Th17 cells or influencing the transcriptional program of dendritic cells. Amongst its tumor-promoting roles, the ImP has a predictive carcinogenic role in some cancers and degrades various tumor-suppressor proteins. The ImP also drives oncogenic inflammation in colitis-associated cancers. It may also increase immune cell infiltration in the TME and trigger danger-associated molecular patterns (DAMPs).