NRG-LU001: A phase II trial investigating metformin as a chemo-radio-sensitizer in locally advanced non-small cell lung cancer (NSCLC)

Abstract

Significantly reduced expression of immunoproteasome components and their regulators was observed to be associated with epithelial to mesenchymal transition in 42 NSCLC cell lines using proteomic profiling and microarray analysis. A highly variable immunoproteasome expression was also observed among NSCLC tissues. Immunohistochemistry data revealed loss of immunoproteasome subunit is significantly correlated with expression of CDH2 and concomitant loss of CDH1 in NSCLC tumors. Loss of immunoproteasome subunits was also significantly associated with advanced stage (p1⁄40.014), recurrence (p1⁄40.002) and metastasis (p<0.01) in NSCLC patients. A significantly reduced antigen presentation was observed in mesenchymal cell lines compared to epithelial cells. Using mild acid elution, only 50-60 HLA class I bound peptides were identified in mesenchymal cell lines compared to 400-500 peptides in epithelial counterparts. IFNg as well as 5-aza-2’-deoxycytidine treatment was able to revive immunoproteasome expression and hence restored repertoire of HLA class I bound peptides in deficient mesenchymal cells. Induced expression of immunoproteasome and hence HLA class I bound peptides also lead to significantly enhanced CD8þ T cell mediated cytotoxicity (p<0.01) in mesenchymal cells compared to non-induced controls. Our findings point towards 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 these cell types.