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Review
. 2021 Dec 20;10(12):3587.
doi: 10.3390/cells10123587.

The Functional and Mechanistic Roles of Immunoproteasome Subunits in Cancer

Satyendra Chandra Tripathi  1 , Disha Vedpathak  1 , Edwin Justin Ostrin  2
Affiliations
Review

The Functional and Mechanistic Roles of Immunoproteasome Subunits in Cancer

Satyendra Chandra Tripathi et al. Cells. .

Abstract

Cell-mediated immunity is driven by antigenic peptide presentation on major histocompatibility complex (MHC) molecules. Specialized proteasome complexes called immunoproteasomes process viral, bacterial, and tumor antigens for presentation on MHC class I molecules, which can induce CD8 T cells to mount effective immune responses. Immunoproteasomes are distinguished by three subunits that alter the catalytic activity of the proteasome and are inducible by inflammatory stimuli such as interferon-γ (IFN-γ). This inducible activity places them in central roles in cancer, autoimmunity, and inflammation. While accelerated proteasomal degradation is an important tumorigenic mechanism deployed by several cancers, there is some ambiguity regarding the role of immunoproteasome induction in neoplastic transformation. Understanding the mechanistic and functional relevance of the immunoproteasome provides essential insights into developing targeted therapies, including overcoming resistance to standard proteasome inhibition and immunomodulation of the tumor microenvironment. In this review, we discuss the roles of the immunoproteasome in different cancers.

Keywords: immunoproteasome; proteasome inhibitors; solid tumors; ubiquitin–proteasome system (UPS).

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic overview depicting various mechanisms of immunoproteasome participation in different cancers. Immunoproteasome can promote or inhibit tumorigenesis in various cancers through distinct and often contradictory mechanisms. In the colon, immunoproteasomal mediated degradation of IκB allows the generation of pro-inflammatory signals that eventually lead to neoplastic transformation of colonic epithelial cells. In melanoma, the inflammatory stimulus of IFN-γ increases the tumor antigen presentation and T cell infiltration, culminating in tumor cell death. In chronic myelogenous leukemia, the early myeloid cells have increased susceptibility to CML if they possess SNPs in the immunoproteasome subunit genes. In ovarian cancer cells, epigenetic modification of CpG islands promotes CD8 T cell migration into the tumor and induces CTL-mediated tumor killing. In non-small cell lung carcinoma, EMT is responsible for reducing immunoproteasome expression, thereby facilitating immune escape due to loss of MHC class I antigen presentation. EMT: epithelial to mesenchymal transition, IP: immunoproteasome, CTL: cytotoxic T lymphocytes.
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