CD28 expressed on malignant plasma cells induces a prosurvival and immunosuppressive microenvironment

Jayakumar R. Nair, Louise M. Carlson, Chandana Koorella, Cheryl H. Rozanski, Gerald E. Byrne, Peter Leif Bergsagel, John P. Shaughnessy, Lawrence H. Boise, Asher A Chanan Khan, Kelvin P. Lee

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

Interactions between the malignant plasma cells of multiple myeloma and stromal cells within the bone marrow microenvironment are essential for myeloma cell survival, mirroring the same dependence of normal bone marrow-resident long-lived plasma cells on specific marrow niches. These interactions directly transduce prosurvival signals to the myeloma cells and also induce niche production of supportive soluble factors. However, despite their central importance, the specific molecular and cellular components involved remain poorly characterized. We now report that the prototypic T cell costimulatory receptor CD28 is overexpressed on myeloma cells during disease progression and in the poor-prognosis subgroups and plays a previously unrecognized role as a two-way molecular bridge to support myeloid stromal cells in the microenvironment. Engagement by CD28 to its ligand CD80/CD86 on stromal dendritic cell directly transduces a prosurvival signal to myeloma cell, protecting it against chemotherapy and growth factor withdrawal-induced death. Simultaneously, CD28-mediated ligation of CD80/CD86 induces the stromal dendritic cell to produce the prosurvival cytokine IL-6 (involving novel cross-talk with the Notch pathway) and the immunosuppressive enzyme IDO. These findings identify CD28 and CD80/CD86 as important molecular components of the interaction between myeloma cells and the bone marrow microenvironment, point to similar interaction for normal plasma cells, and suggest novel therapeutic strategies to target malignant and pathogenic (e.g., in allergy and autoimmunity) plasma cells.

Original languageEnglish (US)
Pages (from-to)1243-1253
Number of pages11
JournalJournal of Immunology
Volume187
Issue number3
DOIs
StatePublished - Aug 1 2011

Fingerprint

Immunosuppressive Agents
Stromal Cells
Plasma Cells
Multiple Myeloma
Dendritic Cells
Costimulatory and Inhibitory T-Cell Receptors
Bone Marrow
Cellular Microenvironment
Myeloid Cells
Autoimmunity
Mesenchymal Stromal Cells
Bone Marrow Cells
Ligation
Disease Progression
Interleukin-6
Cell Survival
Intercellular Signaling Peptides and Proteins
Hypersensitivity
Cytokines
Ligands

ASJC Scopus subject areas

  • Immunology

Cite this

Nair, J. R., Carlson, L. M., Koorella, C., Rozanski, C. H., Byrne, G. E., Bergsagel, P. L., ... Lee, K. P. (2011). CD28 expressed on malignant plasma cells induces a prosurvival and immunosuppressive microenvironment. Journal of Immunology, 187(3), 1243-1253. https://doi.org/10.4049/jimmunol.1100016

CD28 expressed on malignant plasma cells induces a prosurvival and immunosuppressive microenvironment. / Nair, Jayakumar R.; Carlson, Louise M.; Koorella, Chandana; Rozanski, Cheryl H.; Byrne, Gerald E.; Bergsagel, Peter Leif; Shaughnessy, John P.; Boise, Lawrence H.; Chanan Khan, Asher A; Lee, Kelvin P.

In: Journal of Immunology, Vol. 187, No. 3, 01.08.2011, p. 1243-1253.

Research output: Contribution to journalArticle

Nair, JR, Carlson, LM, Koorella, C, Rozanski, CH, Byrne, GE, Bergsagel, PL, Shaughnessy, JP, Boise, LH, Chanan Khan, AA & Lee, KP 2011, 'CD28 expressed on malignant plasma cells induces a prosurvival and immunosuppressive microenvironment', Journal of Immunology, vol. 187, no. 3, pp. 1243-1253. https://doi.org/10.4049/jimmunol.1100016
Nair, Jayakumar R. ; Carlson, Louise M. ; Koorella, Chandana ; Rozanski, Cheryl H. ; Byrne, Gerald E. ; Bergsagel, Peter Leif ; Shaughnessy, John P. ; Boise, Lawrence H. ; Chanan Khan, Asher A ; Lee, Kelvin P. / CD28 expressed on malignant plasma cells induces a prosurvival and immunosuppressive microenvironment. In: Journal of Immunology. 2011 ; Vol. 187, No. 3. pp. 1243-1253.
@article{965dc15830844abaad8653e21b415393,
title = "CD28 expressed on malignant plasma cells induces a prosurvival and immunosuppressive microenvironment",
abstract = "Interactions between the malignant plasma cells of multiple myeloma and stromal cells within the bone marrow microenvironment are essential for myeloma cell survival, mirroring the same dependence of normal bone marrow-resident long-lived plasma cells on specific marrow niches. These interactions directly transduce prosurvival signals to the myeloma cells and also induce niche production of supportive soluble factors. However, despite their central importance, the specific molecular and cellular components involved remain poorly characterized. We now report that the prototypic T cell costimulatory receptor CD28 is overexpressed on myeloma cells during disease progression and in the poor-prognosis subgroups and plays a previously unrecognized role as a two-way molecular bridge to support myeloid stromal cells in the microenvironment. Engagement by CD28 to its ligand CD80/CD86 on stromal dendritic cell directly transduces a prosurvival signal to myeloma cell, protecting it against chemotherapy and growth factor withdrawal-induced death. Simultaneously, CD28-mediated ligation of CD80/CD86 induces the stromal dendritic cell to produce the prosurvival cytokine IL-6 (involving novel cross-talk with the Notch pathway) and the immunosuppressive enzyme IDO. These findings identify CD28 and CD80/CD86 as important molecular components of the interaction between myeloma cells and the bone marrow microenvironment, point to similar interaction for normal plasma cells, and suggest novel therapeutic strategies to target malignant and pathogenic (e.g., in allergy and autoimmunity) plasma cells.",
author = "Nair, {Jayakumar R.} and Carlson, {Louise M.} and Chandana Koorella and Rozanski, {Cheryl H.} and Byrne, {Gerald E.} and Bergsagel, {Peter Leif} and Shaughnessy, {John P.} and Boise, {Lawrence H.} and {Chanan Khan}, {Asher A} and Lee, {Kelvin P.}",
year = "2011",
month = "8",
day = "1",
doi = "10.4049/jimmunol.1100016",
language = "English (US)",
volume = "187",
pages = "1243--1253",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "3",

}

TY - JOUR

T1 - CD28 expressed on malignant plasma cells induces a prosurvival and immunosuppressive microenvironment

AU - Nair, Jayakumar R.

AU - Carlson, Louise M.

AU - Koorella, Chandana

AU - Rozanski, Cheryl H.

AU - Byrne, Gerald E.

AU - Bergsagel, Peter Leif

AU - Shaughnessy, John P.

AU - Boise, Lawrence H.

AU - Chanan Khan, Asher A

AU - Lee, Kelvin P.

PY - 2011/8/1

Y1 - 2011/8/1

N2 - Interactions between the malignant plasma cells of multiple myeloma and stromal cells within the bone marrow microenvironment are essential for myeloma cell survival, mirroring the same dependence of normal bone marrow-resident long-lived plasma cells on specific marrow niches. These interactions directly transduce prosurvival signals to the myeloma cells and also induce niche production of supportive soluble factors. However, despite their central importance, the specific molecular and cellular components involved remain poorly characterized. We now report that the prototypic T cell costimulatory receptor CD28 is overexpressed on myeloma cells during disease progression and in the poor-prognosis subgroups and plays a previously unrecognized role as a two-way molecular bridge to support myeloid stromal cells in the microenvironment. Engagement by CD28 to its ligand CD80/CD86 on stromal dendritic cell directly transduces a prosurvival signal to myeloma cell, protecting it against chemotherapy and growth factor withdrawal-induced death. Simultaneously, CD28-mediated ligation of CD80/CD86 induces the stromal dendritic cell to produce the prosurvival cytokine IL-6 (involving novel cross-talk with the Notch pathway) and the immunosuppressive enzyme IDO. These findings identify CD28 and CD80/CD86 as important molecular components of the interaction between myeloma cells and the bone marrow microenvironment, point to similar interaction for normal plasma cells, and suggest novel therapeutic strategies to target malignant and pathogenic (e.g., in allergy and autoimmunity) plasma cells.

AB - Interactions between the malignant plasma cells of multiple myeloma and stromal cells within the bone marrow microenvironment are essential for myeloma cell survival, mirroring the same dependence of normal bone marrow-resident long-lived plasma cells on specific marrow niches. These interactions directly transduce prosurvival signals to the myeloma cells and also induce niche production of supportive soluble factors. However, despite their central importance, the specific molecular and cellular components involved remain poorly characterized. We now report that the prototypic T cell costimulatory receptor CD28 is overexpressed on myeloma cells during disease progression and in the poor-prognosis subgroups and plays a previously unrecognized role as a two-way molecular bridge to support myeloid stromal cells in the microenvironment. Engagement by CD28 to its ligand CD80/CD86 on stromal dendritic cell directly transduces a prosurvival signal to myeloma cell, protecting it against chemotherapy and growth factor withdrawal-induced death. Simultaneously, CD28-mediated ligation of CD80/CD86 induces the stromal dendritic cell to produce the prosurvival cytokine IL-6 (involving novel cross-talk with the Notch pathway) and the immunosuppressive enzyme IDO. These findings identify CD28 and CD80/CD86 as important molecular components of the interaction between myeloma cells and the bone marrow microenvironment, point to similar interaction for normal plasma cells, and suggest novel therapeutic strategies to target malignant and pathogenic (e.g., in allergy and autoimmunity) plasma cells.

UR - http://www.scopus.com/inward/record.url?scp=80051616648&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80051616648&partnerID=8YFLogxK

U2 - 10.4049/jimmunol.1100016

DO - 10.4049/jimmunol.1100016

M3 - Article

C2 - 21715687

AN - SCOPUS:80051616648

VL - 187

SP - 1243

EP - 1253

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 3

ER -