Grp94 in complexes with IgG is a soluble diagnostic marker of gastrointestinal tumors and displays immune-stimulating activity on peripheral blood immune cells

// Elisa Tramentozzi 1 , Erlis Ruli 2 , Imerio Angriman 3 , Romeo Bardini 3 , Michela Campora 4 , Vincenza Guzzardo 7 , Rita Zamarchi 5 , Elisabetta Rossi 6 , Massimo Rugge 7 , Paola Finotti 8 1 Department of Biology, University of Padua, 35121 Padua, Italy 2 Department of Statistical Sciences, University of Padua, 35121 Padua, Italy 3 Division of General Surgery, University of Padua, 35121 Padua, Italy 4 Department of Surgical and Diagnostic Sciences (DISC), University of Genova, 16132 Genova, Italy 5 Istituto Oncologico Veneto IOV, I.R.C.C.S., 35128 Padua, Italy 6 Department of Surgery, Oncology and Gastroenterology, Oncology Section, University of Padova, Padova, Italy & IOV-IRCCS, Padova, Italy 7 Department of Medicine, DMED, University of Padua, 35121 Padua, Italy 8 Department of Pharmaceutical and Pharmacological Sciences, University of Padua, 35131 Padua, Italy Correspondence to: Paola Finotti, email: paola.finotti@unipd.it Keywords: gastrointestinal neoplasms, heat shock proteins, immunoglobulins, immunomodulation, biomarkers Received: March 23, 2016      Accepted: September 12, 2016      Published: September 20, 2016 ABSTRACT Glucose-regulated protein94 (Grp94), the most represented endoplasmic reticulum (ER)-resident heat shock protein (HSP), is a tumor antigen shared by different types of solid and hematological tumors. The tumor-specific feature of Grp94 is its translocation from the ER to the cell surface where it displays pro-oncogenic functions. This un-physiological location has important implications for both the tumor pathology and anti-tumor therapy. We wanted to address the question of whether Grp94 could be measured as liquid marker in cancer patients in order to make predictions of diagnostic and therapeutic relevance for the tumor. To this aim, we performed an in-depth investigation on patients with primary tumors of the gastrointestinal (GI) tract, using different methodological approaches to detect Grp94 in tumor tissues, plasma and peripheral blood mononuclear cells (PBMCs). Results indicate that Grp94 is not only the antigen highly expressed in any tumor tissue and in cells of tumor infiltrates, mostly B lymphocytes, but it is also found in the circulation. However, the only form in which Grp94 was detected in the plasma of any patients and in B lymphocytes induced to proliferate, was that of stable complexes with Immunoglobulin (Ig)G. Using a specific immune-enzyme assay to measure plasma Grp94-IgG complexes, we showed that Grp94-IgG complexes were significantly increased in cancer patients compared to healthy control subjects, serving as diagnostic tumor biomarker. Results also demonstrate that the stimulation of patient PBMCs with Grp94-IgG complexes led to an increased secretion of inflammatory cytokines that might drive a potentially beneficial anti-tumor effect.