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

ABSTRACT: 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 two 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 that led to the onset of colitis-associated carcinogenesies (CAC). In ulcerative colitis (UC) patients with high risk for CAC, immunoproteasome-induced pro-tumorigenic mediators were highly upregulated. Interestingly, the role for the same enzymatic complex in melanoma tumors is relatively unknown. We found that the high expression of immunoproteasomes in human melanoma was associated with better prognosis. Our data revealed that the immunoproteasome has a strong anti-tumorigenic function in cancer types with non-inflammatory microenvironment such as melanoma. CD8+ cytotoxic T lymphocytes (CTLs) from immunoproteasome-deficient mice were reduced during T cell homeostasis and were not able to combat melanoma efficiently. Our results indicate that the immunoproteasome exhibits either pro- or anti-tumoral properties in a context-dependent manner.

ORGANISM(S): Homo sapiens

PROVIDER: GSE150979 | GEO | 2021/08/18

REPOSITORIES: GEO

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Immunoproteasome dysfunction augments alternative polarization of alveolar macrophages

Project description:The proteasome is a central regulatory hub for intracellular signaling by degrading numerous signaling mediators. Immunoproteasomes are specialized types of proteasomes known to be involved in shaping adaptive immune responses, but their role for innate immune signaling is elusive. Here, we analyzed immunoproteasome function for polarization of alveolar macrophages which are highly specialized tissue macrophages of the alveolar surface of the lung. Classical activation (M1 polarization) of primary alveolar macrophages by LPS/IFNÎ³ transcriptionally induced all three immunoproteasome subunits LMP2, LMP7, and MECL-1. In contrast, IL-4 triggered alternative (M2) activation was accompanied by posttranscriptional upregulation of LMP2 and LMP7. Accordingly, immunoproteasome activity increased in M1 cells, and to some extent under M2 conditions. Analyzing the polarization capability from LMP7 deficient mice revealed no effect on the LPS/IFNÎ³ triggered M1 profile, but uncovered a distorted M2 profile for IL-4 stimulated LMP7-/- alveolar macrophages as characterized by increased M2 marker gene expression and CCL17 cytokine release. This shift in immunoproteasome-dependent M2 polarization was accompanied by amplified AKT/STAT6 activation and IRF4 expression in LMP7-/- alveolar macrophages. IL-13 stimulation of LMP7 deficient cells induced a similar M2 skewed profile and IL4RÎ± protein expression was generally elevated in LMP7-/- alveolar macrophages, indicating that amplified IL4R signaling in immunoproteasome defective cells may contribute to augmented M2 polarization. Importantly, treatment with an LMP7-specific proteasome inhibitor recapitulated the findings of genetic LMP7 inactivation. Our results thus suggest a novel role of immunoproteasome function for regulating innate immune function of macrophages by limiting IL4R expression and signaling. Expression data of M0 and M2 macrophages derived from Lmp7 k.o. and control animals

2016-06-29 | E-GEOD-72000 | biostudies-arrayexpress

Immunoproteasome dysfunction augments alternative polarization of alveolar macrophages

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

Project description:Pro- and anti-tumorigenic capacity of immunoproteasomes in shaping the tumor microenvironment

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