Proteasomes are multi-subunit complexes that degrade intracellular proteins through the ubiquitin-proteasome pathway. The immunoproteasome generates peptides that are particularly suitable for binding onto HLA I molecules, thus facilitating antigen presentation leading to CD8+ T cell responses. Lack of expression or down regulation of the immunoproteasome may contribute to immune evasion through antigen loss. The expression of the immunoproteasome and its impact on antigen presentation in tumors of epithelial origin is not well established. Here, we have investigated the constitutive and induced expression patterns of immunoproteasome subunits in lung cancer and their consequence on antigen presentation. We have also assessed the impact of immunoproteasome expression on prognosis for non-small cell lung carcinoma (NSCLC) patients.
Proteomic profiling of the immunoproteasome in 42 NSCLC cell lines revealed significantly reduced expression of immunoproteasome components and their regulators associated with epithelial to mesenchymal transition. We observed highly variable immunoproteasome expression among NSCLC cell lines and tumor tissues. Immunohistochemistry data revealed loss of immunoproteasome subunit is significantly correlated with loss of E-cadherin and expression of N-cadherin in NSCLC tumors. Loss of immunoproteasome subunits was also significantly associated with advanced stage (p = 0.014), recurrence (p = 0.02) and metastasis (p < 0.01) in NSCLC patients. A very low number of HLA class I bound peptides (n = 50 – 60 peptides) were identified in mesenchymal cell lines compared to their epithelial counterparts (n = 400 – 500 peptides). The reduced repertoire of HLA class I bound peptides in mesenchymal cells deficient in immunoproteasome components was restored with either interferon gamma or 5-aza-2ʹ-deoxycytidine treatment. Induced expression of immunoproteasome and hence HLA I bound peptides also lead to significantly enhanced CD8+ T cell mediated cytotoxicity ( p <0.01) in mesenchymal cells compared to non-induced controls. Our findings point to a mechanism of immune evasion of cells with a mesenchymal phenotype and strategies to overcome their immune evasion through induction of the immunoproteasome or targeting the limited repertoire of peptides presented in common by cells with an epithelial or mesenchymal phenotype.
Citation Format: Satyendra C. Tripathi, Haley L. Peters, Edwin J. Ostrin, Ayumu Taguchi, Hiroyuki Katayama, Hong Wang, Amin Momin, Mohit K. Jolly, Muge Celiktas, Jaime Rodriguez, Carmen Behrens, Ignacio I. Wistuba, Eshel Ben Jacob, Herbert Levine, Jeffrey J. Molldrem, Samir M. Hanash. Immunoproteasome deficiency is a feature of NSCLC with a mesenchymal phenotype and is associated with restricted antigen presentation and poor outcome in patients. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A060.
- ©2016 American Association for Cancer Research.