Heat shock protein gp96 and CD4+ and CD8+ T-lymphocytes expression as prognostic factors in various molecular types of invasive breast carcinoma

Abstract

Breast carcinoma shows extensive clinical and molecular heterogenicity. Glycoprotein gp96 is considered a negative prognostic and predictive factor. Controversy exists over the prognostic role of tumor lymphocytic infiltrates. The goal of this study is to illustrate differences in gp96 and CD4+ and CD8+ T-lymphocytes expression among all immunohistochemical groups of breast carcinoma in relation to the clinical course and outcome of the disease. A retrospective observational study was conducted through processing and analysis of 152 female patient tissue samples previously classified by immunohistochemistry. After immunohistochemical processing, the samples were microscopically analyzed and positive cells were manually calculated in the entire biopsy sample for each patient. In the group of patients with triple negative carcinoma, a significantly higher number of CD4 positive cells in patients with no local recurrence were proven, as well as a significant correlation between a smaller number of CD4 positive cells with a lethal outcome. In the group of patients with Luminal B HER2+ carcinoma, a significantly higher proportion of CD8+ cells in patients with local recurrence were demonstrated. The highest glycoprotein gp96 expression was demonstrated in the group of patients with triple negative carcinoma, while the lowest in patients with Luminal A and Luminal B HER2-carcinoma. This study has shown significantly higher gp96 expression and higher extent of tumor lymphocytic infiltrate in more malignant types of breast carcinoma and represents a significant contribution in affirmation of the prognostic role of these variables.

Hypoxia-Induced Intracellular and Extracellular Heat Shock Protein gp96 Increases Paclitaxel-Resistance and Facilitates Immune Evasion in Breast Cancer

“…Furthermore, through conducting in vitro and in vivo experiments, we found that gp96-containing exosomes increased paclitaxel-resistance in PS-BC cells, hinting that PR-BC cells delivered exosomal gp96 to increase paclitaxel-resistance in PS-BC cells. In addition, previous literatures report that cancer cells derived exosomes interact with immune cells to promote immune evasion during cancer pathogenesis ( 37 – 39 ), and researchers notice that gp96 is considered as biomarker for immune surveillance via influencing CD4 + and CD8 + T-lymphocytes ( 9 , 40 ), which are supported by our results that gp96-containing exosomes suppressed cell viability in the CD8 + T cells, which is the main immune cells that recognize tumor antigens ( 35 , 36 ). Also, we verified that extracellular gp96 triggered pyroptotic cell death in CD8 + T cells, which is indirectly validated by the available information that gp96 activated NLRP3 inflammasome in the antigen presenting cells (APCs) ( 48 ).…”

“…report that non-small cell lung cancer (NSCLC) derived PD-L1 containing exosomes promote CD8 + T cell death ( 35 ). Interestingly, gp96 is reported to be closely associated with immune cells infiltration in BC ( 9 , 40 ). Researchers notice that gp96 affects CD4 + and CD8 + T-lymphocytes in various types of invasive breast carcinoma ( 40 ), and extracellular gp96 has been considered as biomarkers for immune surveillance and immune evasion ( 9 ).…”

“…Interestingly, gp96 is reported to be closely associated with immune cells infiltration in BC ( 9 , 40 ). Researchers notice that gp96 affects CD4 + and CD8 + T-lymphocytes in various types of invasive breast carcinoma ( 40 ), and extracellular gp96 has been considered as biomarkers for immune surveillance and immune evasion ( 9 ). Moreover, recent data suggest that there exist links between hypoxia and immune evasion ( 41 ), and hypoxia-induced extracellular HSPs influences immune surveillance and immune evasion ( 9 ).…”

The Role of Innate Immunity in the Pathogenesis of Breast Cancer

“…A tumor is considered HER2 positive only if it is concluded that the gene which codes for HER2 protein synthesis is amplified[4, 6]. The common denominator of the development of cancer and autoimmune/neurodegenerative diseases is chronic inflammation, where the immunosuppressive environment is crucial [7-9]. Growing evidence supports the hypothesis that the local inflammatory processes modulate the microenvironment, which is the key trigger of the molecular etiopatogenetic mechanisms of tumor development [9-11].…”

“…Inflammation mediators transform normal cells by activating oncogenes or getting rid of the anti-oncogenic activity, inducing tumor progression of preneoplastic lesions, apoptosis resistance, and differentiation [9, 12]. The immunosuppressive microenvironment is largely achieved by the action of infiltrating leukocytes, which constitute a large percentage of cellular populations in tumor tissue [7, 12, 13].…”