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Microenvironment generated during EGFR targeted killing of pancreatic tumor cells by ATC inhibits myeloid-derived suppressor cells through COX2 and PGE(2) dependent pathway

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 Th(1) enr...

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Autores principales: Thakur, Archana, Schalk, Dana, Tomaszewski, Elyse, Kondadasula, Sri Vidya, Yano, Hiroshi, Sarkar, Fazlul H, Lum, Lawrence G
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3608954/
https://www.ncbi.nlm.nih.gov/pubmed/23394575
http://dx.doi.org/10.1186/1479-5876-11-35
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author Thakur, Archana
Schalk, Dana
Tomaszewski, Elyse
Kondadasula, Sri Vidya
Yano, Hiroshi
Sarkar, Fazlul H
Lum, Lawrence G
author_facet Thakur, Archana
Schalk, Dana
Tomaszewski, Elyse
Kondadasula, Sri Vidya
Yano, Hiroshi
Sarkar, Fazlul H
Lum, Lawrence G
author_sort Thakur, Archana
collection PubMed
description 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 Th(1) 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 Th(1) 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 Th(1) 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 Th(1) 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), PGE(2) (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 Th(1) cytokine enriched microenvironment. CONCLUSIONS: These data suggest aATC can suppress MDSC differentiation and attenuation of their suppressive activity through down regulation of COX2, PGE(2) and ARG1 pathway that is potentiated in presence of Th(1) cytokines, suggesting that Th(1) enriching immunotherapy may be beneficial in pancreatic cancer treatment.
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spelling pubmed-36089542013-03-28 Microenvironment generated during EGFR targeted killing of pancreatic tumor cells by ATC inhibits myeloid-derived suppressor cells through COX2 and PGE(2) dependent pathway Thakur, Archana Schalk, Dana Tomaszewski, Elyse Kondadasula, Sri Vidya Yano, Hiroshi Sarkar, Fazlul H Lum, Lawrence G J Transl Med Research 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 Th(1) 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 Th(1) 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 Th(1) 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 Th(1) 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), PGE(2) (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 Th(1) cytokine enriched microenvironment. CONCLUSIONS: These data suggest aATC can suppress MDSC differentiation and attenuation of their suppressive activity through down regulation of COX2, PGE(2) and ARG1 pathway that is potentiated in presence of Th(1) cytokines, suggesting that Th(1) enriching immunotherapy may be beneficial in pancreatic cancer treatment. BioMed Central 2013-02-09 /pmc/articles/PMC3608954/ /pubmed/23394575 http://dx.doi.org/10.1186/1479-5876-11-35 Text en Copyright ©2013 Thakur et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research
Thakur, Archana
Schalk, Dana
Tomaszewski, Elyse
Kondadasula, Sri Vidya
Yano, Hiroshi
Sarkar, Fazlul H
Lum, Lawrence G
Microenvironment generated during EGFR targeted killing of pancreatic tumor cells by ATC inhibits myeloid-derived suppressor cells through COX2 and PGE(2) dependent pathway
title Microenvironment generated during EGFR targeted killing of pancreatic tumor cells by ATC inhibits myeloid-derived suppressor cells through COX2 and PGE(2) dependent pathway
title_full Microenvironment generated during EGFR targeted killing of pancreatic tumor cells by ATC inhibits myeloid-derived suppressor cells through COX2 and PGE(2) dependent pathway
title_fullStr Microenvironment generated during EGFR targeted killing of pancreatic tumor cells by ATC inhibits myeloid-derived suppressor cells through COX2 and PGE(2) dependent pathway
title_full_unstemmed Microenvironment generated during EGFR targeted killing of pancreatic tumor cells by ATC inhibits myeloid-derived suppressor cells through COX2 and PGE(2) dependent pathway
title_short Microenvironment generated during EGFR targeted killing of pancreatic tumor cells by ATC inhibits myeloid-derived suppressor cells through COX2 and PGE(2) dependent pathway
title_sort microenvironment generated during egfr targeted killing of pancreatic tumor cells by atc inhibits myeloid-derived suppressor cells through cox2 and pge(2) dependent pathway
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3608954/
https://www.ncbi.nlm.nih.gov/pubmed/23394575
http://dx.doi.org/10.1186/1479-5876-11-35
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