Bone marrow transplantation generates T cell-dependent control of myeloma in mice

Slavica Vuckovic, Simone A. Minnie, David Smith, Kate H. Gartlan, Thomas S. Watkins, Kate A. Markey, Pamela Mukhopadhyay, Camille Guillerey, Rachel D. Kuns, Kelly R. Locke, Antonia L. Pritchard, Peter A. Johansson, Antiopi Varelias, Ping Zhang, Nicholas D. Huntington, Nicola Waddell, Marta Chesi, John J. Miles, Mark J. Smyth, Geoffrey R. Hill

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Transplantation with autologous hematopoietic progenitors remains an important consolidation treatment for patients with multiple myeloma (MM) and is thought to prolong the disease plateau phase by providing intensive cytoreduction. However, transplantation induces inflammation in the context of profound lymphodepletion that may cause hitherto unexpected immunological effects. We developed preclinical models of bone marrow transplantation (BMT) for MM using Vk∗MYC myeloma-bearing recipient mice and donor mice that were myeloma naive or myeloma experienced to simulate autologous transplantation. Surprisingly, we demonstrated broad induction of T cell-dependent myeloma control, most efficiently from memory T cells within myeloma-experienced grafts, but also through priming of naive T cells after BMT. CD8+ T cells from mice with controlled myeloma had a distinct T cell receptor (TCR) repertoire and higher clonotype overlap relative to myeloma-free BMT recipients. Furthermore, T cell-dependent myeloma control could be adoptively transferred to secondary recipients and was myeloma cell clone specific. Interestingly, donor-derived IL-17A acted directly on myeloma cells expressing the IL-17 receptor to induce a transcriptional landscape that promoted tumor growth and immune escape. Conversely, donor IFN-γ secretion and signaling were critical to protective immunity and were profoundly augmented by CD137 agonists. These data provide new insights into the mechanisms of action of transplantation in myeloma and provide rational approaches to improving clinical outcomes.

Original languageEnglish (US)
Article numberCI98888
JournalJournal of Clinical Investigation
Volume129
Issue number1
DOIs
StatePublished - Jan 2 2019

Fingerprint

Bone Marrow Transplantation
T-Lymphocytes
Autologous Transplantation
Tissue Donors
Multiple Myeloma
Interleukin-17 Receptors
Transplantation
Tumor Escape
Interleukin-17
T-Cell Antigen Receptor
Immunity
Clone Cells
Inflammation
Transplants
Growth
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Vuckovic, S., Minnie, S. A., Smith, D., Gartlan, K. H., Watkins, T. S., Markey, K. A., ... Hill, G. R. (2019). Bone marrow transplantation generates T cell-dependent control of myeloma in mice. Journal of Clinical Investigation, 129(1), [CI98888]. https://doi.org/10.1172/JCI98888

Bone marrow transplantation generates T cell-dependent control of myeloma in mice. / Vuckovic, Slavica; Minnie, Simone A.; Smith, David; Gartlan, Kate H.; Watkins, Thomas S.; Markey, Kate A.; Mukhopadhyay, Pamela; Guillerey, Camille; Kuns, Rachel D.; Locke, Kelly R.; Pritchard, Antonia L.; Johansson, Peter A.; Varelias, Antiopi; Zhang, Ping; Huntington, Nicholas D.; Waddell, Nicola; Chesi, Marta; Miles, John J.; Smyth, Mark J.; Hill, Geoffrey R.

In: Journal of Clinical Investigation, Vol. 129, No. 1, CI98888, 02.01.2019.

Research output: Contribution to journalArticle

Vuckovic, S, Minnie, SA, Smith, D, Gartlan, KH, Watkins, TS, Markey, KA, Mukhopadhyay, P, Guillerey, C, Kuns, RD, Locke, KR, Pritchard, AL, Johansson, PA, Varelias, A, Zhang, P, Huntington, ND, Waddell, N, Chesi, M, Miles, JJ, Smyth, MJ & Hill, GR 2019, 'Bone marrow transplantation generates T cell-dependent control of myeloma in mice', Journal of Clinical Investigation, vol. 129, no. 1, CI98888. https://doi.org/10.1172/JCI98888
Vuckovic S, Minnie SA, Smith D, Gartlan KH, Watkins TS, Markey KA et al. Bone marrow transplantation generates T cell-dependent control of myeloma in mice. Journal of Clinical Investigation. 2019 Jan 2;129(1). CI98888. https://doi.org/10.1172/JCI98888
Vuckovic, Slavica ; Minnie, Simone A. ; Smith, David ; Gartlan, Kate H. ; Watkins, Thomas S. ; Markey, Kate A. ; Mukhopadhyay, Pamela ; Guillerey, Camille ; Kuns, Rachel D. ; Locke, Kelly R. ; Pritchard, Antonia L. ; Johansson, Peter A. ; Varelias, Antiopi ; Zhang, Ping ; Huntington, Nicholas D. ; Waddell, Nicola ; Chesi, Marta ; Miles, John J. ; Smyth, Mark J. ; Hill, Geoffrey R. / Bone marrow transplantation generates T cell-dependent control of myeloma in mice. In: Journal of Clinical Investigation. 2019 ; Vol. 129, No. 1.
@article{de4ff5c5486141c0acd210ae50d2ba32,
title = "Bone marrow transplantation generates T cell-dependent control of myeloma in mice",
abstract = "Transplantation with autologous hematopoietic progenitors remains an important consolidation treatment for patients with multiple myeloma (MM) and is thought to prolong the disease plateau phase by providing intensive cytoreduction. However, transplantation induces inflammation in the context of profound lymphodepletion that may cause hitherto unexpected immunological effects. We developed preclinical models of bone marrow transplantation (BMT) for MM using Vk∗MYC myeloma-bearing recipient mice and donor mice that were myeloma naive or myeloma experienced to simulate autologous transplantation. Surprisingly, we demonstrated broad induction of T cell-dependent myeloma control, most efficiently from memory T cells within myeloma-experienced grafts, but also through priming of naive T cells after BMT. CD8+ T cells from mice with controlled myeloma had a distinct T cell receptor (TCR) repertoire and higher clonotype overlap relative to myeloma-free BMT recipients. Furthermore, T cell-dependent myeloma control could be adoptively transferred to secondary recipients and was myeloma cell clone specific. Interestingly, donor-derived IL-17A acted directly on myeloma cells expressing the IL-17 receptor to induce a transcriptional landscape that promoted tumor growth and immune escape. Conversely, donor IFN-γ secretion and signaling were critical to protective immunity and were profoundly augmented by CD137 agonists. These data provide new insights into the mechanisms of action of transplantation in myeloma and provide rational approaches to improving clinical outcomes.",
author = "Slavica Vuckovic and Minnie, {Simone A.} and David Smith and Gartlan, {Kate H.} and Watkins, {Thomas S.} and Markey, {Kate A.} and Pamela Mukhopadhyay and Camille Guillerey and Kuns, {Rachel D.} and Locke, {Kelly R.} and Pritchard, {Antonia L.} and Johansson, {Peter A.} and Antiopi Varelias and Ping Zhang and Huntington, {Nicholas D.} and Nicola Waddell and Marta Chesi and Miles, {John J.} and Smyth, {Mark J.} and Hill, {Geoffrey R.}",
year = "2019",
month = "1",
day = "2",
doi = "10.1172/JCI98888",
language = "English (US)",
volume = "129",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "1",

}

TY - JOUR

T1 - Bone marrow transplantation generates T cell-dependent control of myeloma in mice

AU - Vuckovic, Slavica

AU - Minnie, Simone A.

AU - Smith, David

AU - Gartlan, Kate H.

AU - Watkins, Thomas S.

AU - Markey, Kate A.

AU - Mukhopadhyay, Pamela

AU - Guillerey, Camille

AU - Kuns, Rachel D.

AU - Locke, Kelly R.

AU - Pritchard, Antonia L.

AU - Johansson, Peter A.

AU - Varelias, Antiopi

AU - Zhang, Ping

AU - Huntington, Nicholas D.

AU - Waddell, Nicola

AU - Chesi, Marta

AU - Miles, John J.

AU - Smyth, Mark J.

AU - Hill, Geoffrey R.

PY - 2019/1/2

Y1 - 2019/1/2

N2 - Transplantation with autologous hematopoietic progenitors remains an important consolidation treatment for patients with multiple myeloma (MM) and is thought to prolong the disease plateau phase by providing intensive cytoreduction. However, transplantation induces inflammation in the context of profound lymphodepletion that may cause hitherto unexpected immunological effects. We developed preclinical models of bone marrow transplantation (BMT) for MM using Vk∗MYC myeloma-bearing recipient mice and donor mice that were myeloma naive or myeloma experienced to simulate autologous transplantation. Surprisingly, we demonstrated broad induction of T cell-dependent myeloma control, most efficiently from memory T cells within myeloma-experienced grafts, but also through priming of naive T cells after BMT. CD8+ T cells from mice with controlled myeloma had a distinct T cell receptor (TCR) repertoire and higher clonotype overlap relative to myeloma-free BMT recipients. Furthermore, T cell-dependent myeloma control could be adoptively transferred to secondary recipients and was myeloma cell clone specific. Interestingly, donor-derived IL-17A acted directly on myeloma cells expressing the IL-17 receptor to induce a transcriptional landscape that promoted tumor growth and immune escape. Conversely, donor IFN-γ secretion and signaling were critical to protective immunity and were profoundly augmented by CD137 agonists. These data provide new insights into the mechanisms of action of transplantation in myeloma and provide rational approaches to improving clinical outcomes.

AB - Transplantation with autologous hematopoietic progenitors remains an important consolidation treatment for patients with multiple myeloma (MM) and is thought to prolong the disease plateau phase by providing intensive cytoreduction. However, transplantation induces inflammation in the context of profound lymphodepletion that may cause hitherto unexpected immunological effects. We developed preclinical models of bone marrow transplantation (BMT) for MM using Vk∗MYC myeloma-bearing recipient mice and donor mice that were myeloma naive or myeloma experienced to simulate autologous transplantation. Surprisingly, we demonstrated broad induction of T cell-dependent myeloma control, most efficiently from memory T cells within myeloma-experienced grafts, but also through priming of naive T cells after BMT. CD8+ T cells from mice with controlled myeloma had a distinct T cell receptor (TCR) repertoire and higher clonotype overlap relative to myeloma-free BMT recipients. Furthermore, T cell-dependent myeloma control could be adoptively transferred to secondary recipients and was myeloma cell clone specific. Interestingly, donor-derived IL-17A acted directly on myeloma cells expressing the IL-17 receptor to induce a transcriptional landscape that promoted tumor growth and immune escape. Conversely, donor IFN-γ secretion and signaling were critical to protective immunity and were profoundly augmented by CD137 agonists. These data provide new insights into the mechanisms of action of transplantation in myeloma and provide rational approaches to improving clinical outcomes.

UR - http://www.scopus.com/inward/record.url?scp=85059367411&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85059367411&partnerID=8YFLogxK

U2 - 10.1172/JCI98888

DO - 10.1172/JCI98888

M3 - Article

C2 - 30300141

AN - SCOPUS:85059367411

VL - 129

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 1

M1 - CI98888

ER -