Cancer-associated oxidoreductase ERO1-α promotes immune escape through up-regulation of PD-L1 in human breast cancer

Many human cancers have been reported to have enhanced expression of the immune checkpoint molecule programmed death-ligand 1 (PD-L1), which binds to programmed cell death-1 (PD-1) expressed on immune cells. PD-L1/PD-1 plays a role in inhibition of antitumor immunity by inducing T cell apoptosis and tolerance. Thus, it is crucial to elucidate mechanisms of PD-L1 expression on cancer cells. ERO1-alpha is an oxidase located in the endoplasmic reticulum. It is overexpressed in a variety of tumor types and it plays a role in disulfide bond formation in collaboration with PDI. Here, we investigated the influence of ERO1-alpha on expression of PD-L1 and immune escape. We demonstrated that ERO1-alpha augmented the expression of PD-L1 via facilitation of oxidative protein folding within PD-L1. In addition, we showed that overexpression of ERO1-alpha increased HIF-1 alpha protein expression, resulting in an increase of PD-L1 mRNA as well as protein. In clinical cases, we observed that the expression of ERO1-alpha in triple negative breast cancer was related to the expression of PD-L1. Moreover, apoptosis of Jurkat leukemia T cells, which express PD-1, induced by tumor PD-L1 was inhibited when ERO1-alpha was depleted. The results suggest that targeting ERO1-alpha in tumor cells can be a novel approach for cancer immunotherapy. Therefore, the role of ERO1-alpha in tumor-mediated immunosuppression should be further explored

Clinical Survey of the Results on Colorectal Surgery in the Elderly

From 1978 to 1996, 69 patients who were 80 years of age or older (Group Ⅰ), 75 patients who were between 75 and 79 years of age (Group Ⅱ) and 618 patients who were between 50 and 69 years of age (Group Ⅲ) received surgical treatment for colorectal cancer in our department, A retrospective comparative study of the three groups was made to assess the relevant pathological and surgical factors, preoperative co-existent disease and postoperative complications, postoperative mortality and survival rates, Statistically significant differences were observed in lymph node dissection, the frequency of preoperative co-existent disease, and the frequency of total postoperative complications between Group Ⅰ and Group Ⅲ. The total perioperative mortality rates and 3 years survival rates of the three groups were not significantly different, These results led us to the conclusion that a better prognosis for elderly patients can be achieved if surgery is performed.Therefore, better management and a better rationale governing operative procedures are needed for the treatment of colorectal cance

Heat shock protein 90 targets a chaperoned peptide to the static early endosome for efficient cross-presentation by human dendritic cells

The presentation of an exogenous antigen in a major histocompatibility complex class-I- restricted fashion to CD8(+) T cells is called cross-presentation. Heat shock proteins (HSPs) such as Hsp70, gp96, and Hsp90 have been shown to elicit efficient CTL responses by cross-presentation through an as-yet entirely unknown mechanism. Hsp90 is the most abundant cytosolic HSP and is known to act as a molecular chaperone. We have shown that a tumor antigen peptide complexed with Hsp90 could be cross-presented by dendritic cells (DCs) through an endosomal pathway in a murine system. However, it has not been determined whether human DCs also cross-present an Hsp90-peptide complex and induce peptide-specific CTLs. In this study, we found that an Hsp90-cancer antigen peptide complex was efficiently cross-presented by human monocyte-derived DCs and induced peptide-specific CTLs. Furthermore, we observed that the internalized Hsp90-peptide complex was strictly sorted to the Rab5(+), EEA1(+) static early endosome and the Hsp90-chaperoned peptide was processed and bound to MHC class I molecules through an endosome-recycling pathway. Our data indicate that targeting of the antigen to a static early endosome by Hsp90 is essential for efficient cross-presentation