Blocking monocytic myeloid-derived suppressor cell function via anti-DC-HIL/GpNMB antibody restores the in vitro integrity of T cells from cancer patients

Masato Kobayashi, Jin Sung Chung, Muhammad S Beg, Yull E Arriaga, Udit Verma, Kevin D Courtney, John C Mansour, Barbara B Haley, Saad Khan, Yutaka Horiuchi, Vijay Ramani, David Harker, Purva Gopal, Farshid Araghizadeh, Ponciano D Cruz, Kiyoshi Ariizumi

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Abstract

Purpose: Blocking the function of myeloid-derived Results: Patients with metastatic cancer had high blood suppressor cells (MDSC) is an attractive approach for levels of DC-HILþ MDSCs compared with healthy controls. cancer immunotherapy. Having shown DC-HIL/GPNMB Anti-DC-HIL mAb reversed the in vitro function in 80% of to be the T-cell-inhibitory receptor mediating the sup-cancer patients tested, particularly for colon cancer. Despite pressor function of MDSCs, we evaluated the potential very low expression on blood MDSCs, anti-PDL1 mAb was as of anti-DC-HIL mAb as an MDSC-targeting cancer effective as anti-DC-HIL mAb in reversing MDSC function, a treatment. paradoxical phenomenon we found to be due to upregulated Experimental Design: Patients with metastatic cancer expression of PDL1 by T-cell-derived IFNg in cocultures. DC-(n ¼ 198) were analyzed by flow cytometry for DC-HIL or HIL is not expressed by colorectal cancer cells but by CD14þ PDL1 expression on blood CD14þHLA-DRno/lo MDSCs. cells infiltrating the tumor. Finally, anti-DC-HIL mAb atten-Their suppressor function was assessed by in vitro co-uated growth of preestablished colon tumors by reducing culture with autologous T cells, and the ability of anti-MDSCs and increasing IFNg-secreting T cells in the tumor DC-HIL or anti-PDL1 mAb to reverse such function was microenvironment, with similar outcomes to anti-PDL1 mAb. determined. Tumor expression of these receptors was exam-Conclusions: Blocking DC-HIL function is a potentially use-ined histologically, and the antitumor activity of the mAb ful treatment for at least colorectal cancer with high blood levels was evaluated by attenuated growth of colon cancers in of DC-HILþ MDSCs.

Original languageEnglish (US)
Pages (from-to)828-838
Number of pages11
JournalClinical Cancer Research
Volume25
Issue number2
DOIs
StatePublished - Jan 15 2019

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T-Lymphocytes
Antibodies
Neoplasms
Colonic Neoplasms
Colorectal Neoplasms
Costimulatory and Inhibitory T-Cell Receptors
Myeloid-Derived Suppressor Cells
In Vitro Techniques
Growth
Coculture Techniques
Immunotherapy
Blood Cells
Flow Cytometry
Colon
Research Design
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

@article{84f506128f6c4f328952dd6dbacc0fbd,
title = "Blocking monocytic myeloid-derived suppressor cell function via anti-DC-HIL/GpNMB antibody restores the in vitro integrity of T cells from cancer patients",
abstract = "Purpose: Blocking the function of myeloid-derived Results: Patients with metastatic cancer had high blood suppressor cells (MDSC) is an attractive approach for levels of DC-HIL{\th} MDSCs compared with healthy controls. cancer immunotherapy. Having shown DC-HIL/GPNMB Anti-DC-HIL mAb reversed the in vitro function in 80{\%} of to be the T-cell-inhibitory receptor mediating the sup-cancer patients tested, particularly for colon cancer. Despite pressor function of MDSCs, we evaluated the potential very low expression on blood MDSCs, anti-PDL1 mAb was as of anti-DC-HIL mAb as an MDSC-targeting cancer effective as anti-DC-HIL mAb in reversing MDSC function, a treatment. paradoxical phenomenon we found to be due to upregulated Experimental Design: Patients with metastatic cancer expression of PDL1 by T-cell-derived IFNg in cocultures. DC-(n ¼ 198) were analyzed by flow cytometry for DC-HIL or HIL is not expressed by colorectal cancer cells but by CD14{\th} PDL1 expression on blood CD14{\th}HLA-DRno/lo MDSCs. cells infiltrating the tumor. Finally, anti-DC-HIL mAb atten-Their suppressor function was assessed by in vitro co-uated growth of preestablished colon tumors by reducing culture with autologous T cells, and the ability of anti-MDSCs and increasing IFNg-secreting T cells in the tumor DC-HIL or anti-PDL1 mAb to reverse such function was microenvironment, with similar outcomes to anti-PDL1 mAb. determined. Tumor expression of these receptors was exam-Conclusions: Blocking DC-HIL function is a potentially use-ined histologically, and the antitumor activity of the mAb ful treatment for at least colorectal cancer with high blood levels was evaluated by attenuated growth of colon cancers in of DC-HIL{\th} MDSCs.",
author = "Masato Kobayashi and Chung, {Jin Sung} and Beg, {Muhammad S} and Arriaga, {Yull E} and Udit Verma and Courtney, {Kevin D} and Mansour, {John C} and Haley, {Barbara B} and Saad Khan and Yutaka Horiuchi and Vijay Ramani and David Harker and Purva Gopal and Farshid Araghizadeh and Cruz, {Ponciano D} and Kiyoshi Ariizumi",
year = "2019",
month = "1",
day = "15",
doi = "10.1158/1078-0432.CCR-18-0330",
language = "English (US)",
volume = "25",
pages = "828--838",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "2",

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TY - JOUR

T1 - Blocking monocytic myeloid-derived suppressor cell function via anti-DC-HIL/GpNMB antibody restores the in vitro integrity of T cells from cancer patients

AU - Kobayashi, Masato

AU - Chung, Jin Sung

AU - Beg, Muhammad S

AU - Arriaga, Yull E

AU - Verma, Udit

AU - Courtney, Kevin D

AU - Mansour, John C

AU - Haley, Barbara B

AU - Khan, Saad

AU - Horiuchi, Yutaka

AU - Ramani, Vijay

AU - Harker, David

AU - Gopal, Purva

AU - Araghizadeh, Farshid

AU - Cruz, Ponciano D

AU - Ariizumi, Kiyoshi

PY - 2019/1/15

Y1 - 2019/1/15

N2 - Purpose: Blocking the function of myeloid-derived Results: Patients with metastatic cancer had high blood suppressor cells (MDSC) is an attractive approach for levels of DC-HILþ MDSCs compared with healthy controls. cancer immunotherapy. Having shown DC-HIL/GPNMB Anti-DC-HIL mAb reversed the in vitro function in 80% of to be the T-cell-inhibitory receptor mediating the sup-cancer patients tested, particularly for colon cancer. Despite pressor function of MDSCs, we evaluated the potential very low expression on blood MDSCs, anti-PDL1 mAb was as of anti-DC-HIL mAb as an MDSC-targeting cancer effective as anti-DC-HIL mAb in reversing MDSC function, a treatment. paradoxical phenomenon we found to be due to upregulated Experimental Design: Patients with metastatic cancer expression of PDL1 by T-cell-derived IFNg in cocultures. DC-(n ¼ 198) were analyzed by flow cytometry for DC-HIL or HIL is not expressed by colorectal cancer cells but by CD14þ PDL1 expression on blood CD14þHLA-DRno/lo MDSCs. cells infiltrating the tumor. Finally, anti-DC-HIL mAb atten-Their suppressor function was assessed by in vitro co-uated growth of preestablished colon tumors by reducing culture with autologous T cells, and the ability of anti-MDSCs and increasing IFNg-secreting T cells in the tumor DC-HIL or anti-PDL1 mAb to reverse such function was microenvironment, with similar outcomes to anti-PDL1 mAb. determined. Tumor expression of these receptors was exam-Conclusions: Blocking DC-HIL function is a potentially use-ined histologically, and the antitumor activity of the mAb ful treatment for at least colorectal cancer with high blood levels was evaluated by attenuated growth of colon cancers in of DC-HILþ MDSCs.

AB - Purpose: Blocking the function of myeloid-derived Results: Patients with metastatic cancer had high blood suppressor cells (MDSC) is an attractive approach for levels of DC-HILþ MDSCs compared with healthy controls. cancer immunotherapy. Having shown DC-HIL/GPNMB Anti-DC-HIL mAb reversed the in vitro function in 80% of to be the T-cell-inhibitory receptor mediating the sup-cancer patients tested, particularly for colon cancer. Despite pressor function of MDSCs, we evaluated the potential very low expression on blood MDSCs, anti-PDL1 mAb was as of anti-DC-HIL mAb as an MDSC-targeting cancer effective as anti-DC-HIL mAb in reversing MDSC function, a treatment. paradoxical phenomenon we found to be due to upregulated Experimental Design: Patients with metastatic cancer expression of PDL1 by T-cell-derived IFNg in cocultures. DC-(n ¼ 198) were analyzed by flow cytometry for DC-HIL or HIL is not expressed by colorectal cancer cells but by CD14þ PDL1 expression on blood CD14þHLA-DRno/lo MDSCs. cells infiltrating the tumor. Finally, anti-DC-HIL mAb atten-Their suppressor function was assessed by in vitro co-uated growth of preestablished colon tumors by reducing culture with autologous T cells, and the ability of anti-MDSCs and increasing IFNg-secreting T cells in the tumor DC-HIL or anti-PDL1 mAb to reverse such function was microenvironment, with similar outcomes to anti-PDL1 mAb. determined. Tumor expression of these receptors was exam-Conclusions: Blocking DC-HIL function is a potentially use-ined histologically, and the antitumor activity of the mAb ful treatment for at least colorectal cancer with high blood levels was evaluated by attenuated growth of colon cancers in of DC-HILþ MDSCs.

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