Pro- and anti-tumorigenic capacity of immunoproteasomes in shaping the tumor microenvironment.

Apart from the constitutive proteasome, the immunoproteasome that comprises the three proteolytic subunits LMP2, MECL-1, and LMP7 is expressed in most immune cells. In this study, we describe opposing roles for immunoproteasomes in regulating the tumor microenvironment. During chronic inflammation, immunoproteasomes modulated the expression of pro-tumorigenic cytokines and chemokines and enhanced infiltration of innate immune cells, thus triggering the onset of colitis-associated carcinogenesis (CAC) in wild-type (WT) mice. Consequently, immunoproteasome-deficient animals (LMP2/MECL-1/LMP7-null mice) were almost completely resistant to CAC development. In ulcerative colitis (UC) patients with high risk for CAC, immunoproteasome-induced pro-tumorigenic mediators were upregulated. In melanoma tumors, the role of immunoproteasomes is relatively unknown. We found that high expression of immunoproteasomes in human melanoma was associated with better prognosis. Similarly, our data revealed that the immunoproteasome has anti-tumorigenic activity in a mouse model of melanoma. The anti-tumor immunity against melanoma was compromised in immunoproteasome-deficient mice due to the impaired activity of CD8+ cytotoxic T lymphocytes (CTLs), CD4+ Th1 cells, and antigen-presenting cells (APCs). These findings show that immunoproteasomes may exert opposing roles with either pro- or anti-tumoral properties in a context-dependent manner.