High Expression of Calreticulin Affected the Tumor Microenvironment and Correlated With Worse Prognosis in Patients With Triple-Negative Breast Cancer.

Abstract

Calreticulin (CALR) preserves reticular homeostasis by maintaining correct protein folding within the endoplasmic reticulum. Immunogenic cell death (ICD) is a regulated form of cell death and could activate adaptive immune response. As one of the damage-associated molecular patterns during ICD process, surface-exposed CALR resulted in the activation of adaptive immune response. Here, we evaluated the expression patterns of CALR in a cohort of 231 untreated triple-negative breast cancer (TNBC) and determined correlations between CALR expression and clinicopathologic parameters, programmed cell death ligand 1 (PD-L1) expression in immune cells (ICs), and survival. In addition, we analyzed a TNBC data set from The Cancer Genome Atlas to explore the relationship between mRNA expression of CALR and clinicopathologic features, IC infiltration, and survival. Tissue microarray results showed that high CLAR was strongly correlated with advanced stage (P = 0.022), shorter disease-free survival (P = 0.008) and overall survival (P = 0.002), and independently predicted prognosis in TNBC. Spearman analyses demonstrated that CALR negatively correlated with PD-L1 in ICs (r = -0.198, P = 0.003). Patients with low CALR and high PD-L1 in ICs had the best disease-free survival (P = 0.013) and overall survival (P = 0.004) compared with other patients, especially the patients with high CALR and low PD-L1 in ICs. In the "The Cancer Genome Atlas" cohort, CALR mRNA expression in tumors was significantly higher than that in normal tissues (P < 0.001). CALR expression was strongly and positively related to other ICD-related genes. These findings demonstrated that the expression of CALR could independently predict the prognosis in patients with TNBC, and it may play a potential synergistic role in treatments involving immunotherapy.