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Blocking Monocytic Myeloid-Derived Suppressor Cell Function via Anti-DC-HIL/GPNMB Antibody Restores the In Vitro Integrity of T Cells from Cancer Patients.
Kobayashi, Masato; Chung, Jin-Sung; Beg, Muhammad; Arriaga, Yull; Verma, Udit; Courtney, Kevin; Mansour, John; Haley, Barbara; Khan, Saad; Horiuchi, Yutaka; Ramani, Vijay; Harker, David; Gopal, Purva; Araghizadeh, Farshid; Cruz, Ponciano D; Ariizumi, Kiyoshi.
Afiliación
  • Kobayashi M; Department of Dermatology, The University of Texas Southwestern Medical Center, Dallas, Texas.
  • Chung JS; Department of Dermatology, The University of Texas Southwestern Medical Center, Dallas, Texas.
  • Beg M; Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas.
  • Arriaga Y; Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas.
  • Verma U; Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas.
  • Courtney K; Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas.
  • Mansour J; Department of Surgery, The University of Texas Southwestern Medical Center, Dallas, Texas.
  • Haley B; Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas.
  • Khan S; Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas.
  • Horiuchi Y; Department of Microbiology, Faculty of Medicine, Saitama Medical University, Iruma District, Saitama Prefecture, Japan.
  • Ramani V; Department of Dermatology, The University of Texas Southwestern Medical Center, Dallas, Texas.
  • Harker D; Department of Dermatology, The University of Texas Southwestern Medical Center, Dallas, Texas.
  • Gopal P; Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas.
  • Araghizadeh F; Department of Surgery, The University of Texas Southwestern Medical Center, Dallas, Texas.
  • Cruz PD; Department of Dermatology, The University of Texas Southwestern Medical Center, Dallas, Texas.
  • Ariizumi K; Department of Dermatology, The University of Texas Southwestern Medical Center, Dallas, Texas. kiyoshi.ariizumi@utsouthwestern.edu.
Clin Cancer Res ; 25(2): 828-838, 2019 01 15.
Article en En | MEDLINE | ID: mdl-30049749
PURPOSE: Blocking the function of myeloid-derived suppressor cells (MDSC) is an attractive approach for cancer immunotherapy. Having shown DC-HIL/GPNMB to be the T-cell-inhibitory receptor mediating the suppressor function of MDSCs, we evaluated the potential of anti-DC-HIL mAb as an MDSC-targeting cancer treatment. EXPERIMENTAL DESIGN: Patients with metastatic cancer (n = 198) were analyzed by flow cytometry for DC-HIL or PDL1 expression on blood CD14+HLA-DRno/lo MDSCs. Their suppressor function was assessed by in vitro coculture with autologous T cells, and the ability of anti-DC-HIL or anti-PDL1 mAb to reverse such function was determined. Tumor expression of these receptors was examined histologically, and the antitumor activity of the mAb was evaluated by attenuated growth of colon cancers in mice. RESULTS: Patients with metastatic cancer had high blood levels of DC-HIL+ MDSCs compared with healthy controls. Anti-DC-HIL mAb reversed the in vitro function in ∼80% of cancer patients tested, particularly for colon cancer. Despite very low expression on blood MDSCs, anti-PDL1 mAb was as effective as anti-DC-HIL mAb in reversing MDSC function, a paradoxical phenomenon we found to be due to upregulated expression of PDL1 by T-cell-derived IFNγ in cocultures. DC-HIL is not expressed by colorectal cancer cells but by CD14+ cells infiltrating the tumor. Finally, anti-DC-HIL mAb attenuated growth of preestablished colon tumors by reducing MDSCs and increasing IFNγ-secreting T cells in the tumor microenvironment, with similar outcomes to anti-PDL1 mAb. CONCLUSIONS: Blocking DC-HIL function is a potentially useful treatment for at least colorectal cancer with high blood levels of DC-HIL+ MDSCs.See related commentary by Colombo, p. 453.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Glicoproteínas de Membrana / Linfocitos T / Células Supresoras de Origen Mieloide / Antineoplásicos Inmunológicos / Neoplasias Límite: Animals / Humans Idioma: En Revista: Clin Cancer Res Asunto de la revista: NEOPLASIAS Año: 2019 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Glicoproteínas de Membrana / Linfocitos T / Células Supresoras de Origen Mieloide / Antineoplásicos Inmunológicos / Neoplasias Límite: Animals / Humans Idioma: En Revista: Clin Cancer Res Asunto de la revista: NEOPLASIAS Año: 2019 Tipo del documento: Article Pais de publicación: Estados Unidos