Cargando…
Autologous Hematopoietic Stem Cells Are a Preferred Source to Generate Dendritic Cells for Immunotherapy in Multiple Myeloma Patients
In multiple myeloma (MM), dendritic cells (DCs), and their precursors are prone to malignant cell-mediated regulation of function leading to low efficacy of DC vaccine. DCs taken directly from MM patient's body or derived from monocytes are fewer in numbers and are also dysfunctional. Here, we...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536579/ https://www.ncbi.nlm.nih.gov/pubmed/31164886 http://dx.doi.org/10.3389/fimmu.2019.01079 |
_version_ | 1783421779736264704 |
---|---|
author | Shinde, Prajakta Melinkeri, Sameer Santra, Manas Kumar Kale, Vaijayanti Limaye, Lalita |
author_facet | Shinde, Prajakta Melinkeri, Sameer Santra, Manas Kumar Kale, Vaijayanti Limaye, Lalita |
author_sort | Shinde, Prajakta |
collection | PubMed |
description | In multiple myeloma (MM), dendritic cells (DCs), and their precursors are prone to malignant cell-mediated regulation of function leading to low efficacy of DC vaccine. DCs taken directly from MM patient's body or derived from monocytes are fewer in numbers and are also dysfunctional. Here, we investigated the functionality of Hematopoietic stem cell-derived DCs (SC-DCs) from MM patients. Mature-MM-SC-DCs showed all essential functions like antigen uptake, allogenic T cells simulation and migration comparable to those derived from healthy donor (HD) samples. A comparison of Mo-DCs and SC-DCs obtained from the same MM patients' samples revealed that the expression of IL-6 was higher in the precursors of Mo-DCs leading to their impaired migration. In addition, expression of CCR7 which is responsible for DCs migration was found to be lower in MM-Mo-DCs. The chromatin permissiveness as observed by H3K4me(3) histone modification at the Ccr7 promoter in MM-Mo-DCs was significantly lower than those in MM-SC-DCs. Levels of Zbtb46- a hall mark DC transcription factor mRNA was also found to be reduced in MM-Mo-DCs. Cytotoxic T cells generated from MM-SC-DCs from autologous naïve T cells exhibited reduced antitumor activity because the T cells were exhausted. Blocking of CTLA-4 on autologous T cells could partially restore T cell proliferation and activation. Thus, a combination of MM-SC-DC vaccine and anti-CTLA-4 antibody may serve as a better candidate for immunotherapy of MM. This study has implications in increasing the efficacy of cancer immunotherapy in MM. |
format | Online Article Text |
id | pubmed-6536579 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-65365792019-06-04 Autologous Hematopoietic Stem Cells Are a Preferred Source to Generate Dendritic Cells for Immunotherapy in Multiple Myeloma Patients Shinde, Prajakta Melinkeri, Sameer Santra, Manas Kumar Kale, Vaijayanti Limaye, Lalita Front Immunol Immunology In multiple myeloma (MM), dendritic cells (DCs), and their precursors are prone to malignant cell-mediated regulation of function leading to low efficacy of DC vaccine. DCs taken directly from MM patient's body or derived from monocytes are fewer in numbers and are also dysfunctional. Here, we investigated the functionality of Hematopoietic stem cell-derived DCs (SC-DCs) from MM patients. Mature-MM-SC-DCs showed all essential functions like antigen uptake, allogenic T cells simulation and migration comparable to those derived from healthy donor (HD) samples. A comparison of Mo-DCs and SC-DCs obtained from the same MM patients' samples revealed that the expression of IL-6 was higher in the precursors of Mo-DCs leading to their impaired migration. In addition, expression of CCR7 which is responsible for DCs migration was found to be lower in MM-Mo-DCs. The chromatin permissiveness as observed by H3K4me(3) histone modification at the Ccr7 promoter in MM-Mo-DCs was significantly lower than those in MM-SC-DCs. Levels of Zbtb46- a hall mark DC transcription factor mRNA was also found to be reduced in MM-Mo-DCs. Cytotoxic T cells generated from MM-SC-DCs from autologous naïve T cells exhibited reduced antitumor activity because the T cells were exhausted. Blocking of CTLA-4 on autologous T cells could partially restore T cell proliferation and activation. Thus, a combination of MM-SC-DC vaccine and anti-CTLA-4 antibody may serve as a better candidate for immunotherapy of MM. This study has implications in increasing the efficacy of cancer immunotherapy in MM. Frontiers Media S.A. 2019-05-21 /pmc/articles/PMC6536579/ /pubmed/31164886 http://dx.doi.org/10.3389/fimmu.2019.01079 Text en Copyright © 2019 Shinde, Melinkeri, Santra, Kale and Limaye. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Shinde, Prajakta Melinkeri, Sameer Santra, Manas Kumar Kale, Vaijayanti Limaye, Lalita Autologous Hematopoietic Stem Cells Are a Preferred Source to Generate Dendritic Cells for Immunotherapy in Multiple Myeloma Patients |
title | Autologous Hematopoietic Stem Cells Are a Preferred Source to Generate Dendritic Cells for Immunotherapy in Multiple Myeloma Patients |
title_full | Autologous Hematopoietic Stem Cells Are a Preferred Source to Generate Dendritic Cells for Immunotherapy in Multiple Myeloma Patients |
title_fullStr | Autologous Hematopoietic Stem Cells Are a Preferred Source to Generate Dendritic Cells for Immunotherapy in Multiple Myeloma Patients |
title_full_unstemmed | Autologous Hematopoietic Stem Cells Are a Preferred Source to Generate Dendritic Cells for Immunotherapy in Multiple Myeloma Patients |
title_short | Autologous Hematopoietic Stem Cells Are a Preferred Source to Generate Dendritic Cells for Immunotherapy in Multiple Myeloma Patients |
title_sort | autologous hematopoietic stem cells are a preferred source to generate dendritic cells for immunotherapy in multiple myeloma patients |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536579/ https://www.ncbi.nlm.nih.gov/pubmed/31164886 http://dx.doi.org/10.3389/fimmu.2019.01079 |
work_keys_str_mv | AT shindeprajakta autologoushematopoieticstemcellsareapreferredsourcetogeneratedendriticcellsforimmunotherapyinmultiplemyelomapatients AT melinkerisameer autologoushematopoieticstemcellsareapreferredsourcetogeneratedendriticcellsforimmunotherapyinmultiplemyelomapatients AT santramanaskumar autologoushematopoieticstemcellsareapreferredsourcetogeneratedendriticcellsforimmunotherapyinmultiplemyelomapatients AT kalevaijayanti autologoushematopoieticstemcellsareapreferredsourcetogeneratedendriticcellsforimmunotherapyinmultiplemyelomapatients AT limayelalita autologoushematopoieticstemcellsareapreferredsourcetogeneratedendriticcellsforimmunotherapyinmultiplemyelomapatients |