Pro- and Antitumorigenic Capacity of Immunoproteasomes in Shaping the Tumor Microenvironment
Autor: | Hanna Leister, Ulrich Steinhoff, Bernd Schmeck, Maik Luu, Leon N. Schulte, Markus Bosmann, Hans-Joachim Mollenkopf, Daniel Staudenraus, Alexander Visekruna, Wilhelm Bertrams, Aleksandra Lopez Krol, Nils Schmerer, Arjun Sharma |
---|---|
Rok vydání: | 2021 |
Předmět: |
0301 basic medicine
Proteasome Endopeptidase Complex Cancer Research Chemokine Immunology Melanoma Experimental Antineoplastic Agents Inflammation medicine.disease_cause Article Mice 03 medical and health sciences 0302 clinical medicine Immune system Cell Line Tumor Tumor Microenvironment medicine Animals Humans Mice Knockout Tumor microenvironment Innate immune system biology Chemistry Melanoma Histocompatibility Antigens Class I Colitis medicine.disease Mice Inbred C57BL Cysteine Endopeptidases 030104 developmental biology 030220 oncology & carcinogenesis Cancer research biology.protein Cytokines Female medicine.symptom Carcinogenesis CD8 T-Lymphocytes Cytotoxic |
Zdroj: | Cancer Immunol Res |
ISSN: | 2326-6074 2326-6066 |
Popis: | 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 (TME). During chronic inflammation, immunoproteasomes modulated the expression of protumorigenic cytokines and chemokines and enhanced infiltration of innate immune cells, thus triggering the onset of colitis-associated carcinogenesis (CAC) in wild-type mice. Consequently, immunoproteasome-deficient animals (LMP2/MECL-1/LMP7–null mice) were almost completely resistant to CAC development. In patients with ulcerative colitis with high risk for CAC, immunoproteasome-induced protumorigenic 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 antitumorigenic activity in a mouse model of melanoma. The antitumor immunity against melanoma was compromised in immunoproteasome-deficient mice because of the impaired activity of CD8+ CTLs, CD4+ Th1 cells, and antigen-presenting cells. These findings show that immunoproteasomes may exert opposing roles with either pro- or antitumoral properties in a context-dependent manner. |
Databáze: | OpenAIRE |
Externí odkaz: |