title: Microenvironment generated during EGFR targeted killing of pancreatic tumor cells by ATC inhibits myeloid-derived suppressor cells through COX2 and PGE2 dependent pathway.
abstract: BACKGROUND
  Myeloid-derived suppressor cells (MDSCs) are one of the major components of the immune-suppressive network, play key roles in tumor progression and limit therapeutic responses. Recently, we reported that tumor spheres formed by breast cancer cell lines were visibly smaller in a Th1 enriched microenvironment with significantly reduced differentiation of MDSC populations in 3D culture. In this study, we investigated the mechanism(s) of bispecific antibody armed ATC mediated inhibition of MDSC in the presence or absence of Th1 microenvironment.
  
  
  METHODS
  We used 3D co-culture model of peripheral blood mononuclear cells (PBMC) with pancreatic cancer cells MiaPaCa-2 [MiaE] and gemcitabine resistant MiaPaCa-GR [MiaM] cells to generate MDSC in the presence or absence of Th1 cytokines and EGFRBi armed ATC (aATC).
  
  
  RESULTS
  We show significantly decreased differentiation of MDSC (MiaE, p<0.005; MiaM, p<0.05) in the presence of aATC with or without Th1 cytokines. MDSC recovered from control cultures (without aATC) showed potent ability to suppress T cell functions compared to those recovered from aATC containing co-cultures. Reduced accumulation of MDSC was accompanied by significantly lower levels of COX2 (p<0.0048), PGE2 (p<0.03), and their downstream effector molecule Arginase-1 (p<0.01), and significantly higher levels of TNF-α, IL-12 and chemokines CCL3, CCL4, CCL5, CXCL9 and CXCL10 under aATC induced Th1 cytokine enriched microenvironment.
  
  
  CONCLUSIONS
  These data suggest aATC can suppress MDSC differentiation and attenuation of their suppressive activity through down regulation of COX2, PGE2 and ARG1 pathway that is potentiated in presence of Th1 cytokines, suggesting that Th1 enriching immunotherapy may be beneficial in pancreatic cancer treatment.
authors: Departments of Oncology and Medicine, Wayne State University and Barbara Ann Karmanos Cancer Institute, Detroit, MI 48201, USA. thakur@karmanos.org
authors: Archana
authors: A
authors: Thakur
authors: Dana
authors: D
authors: Schalk
authors: Elyse
authors: E
authors: Tomaszewski
authors: Sri Vidya
authors: SV
authors: Kondadasula
authors: Hiroshi
authors: H
authors: Yano
authors: Fazlul H
authors: FH
authors: Sarkar
authors: Lawrence G
authors: LG
authors: Lum
mesh_terms: D002454:Cell Differentiation; D049109:Cell Proliferation; D018920:Coculture Techniques; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D015232:Dinoprostone / Q000096:biosynthesis / Q000378:metabolism*; D066246:ErbB Receptors / Q000187:drug effects*; D005434:Flow Cytometry; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D013601:T-Lymphocytes / Q000276:immunology; D059016:Tumor Microenvironment
chemical_list: D016207:Cytokines; D051546:Cyclooxygenase 2; D066246:ErbB Receptors; D015232:Dinoprostone
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