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Increased Immune-Regulatory Receptor Expression on Effector T Cells as Early Indicators of Relapse Following Autologous Stem Cell Transplantation for Multiple Myeloma

The benefit of autologous stem cell transplantation (ASCT) in newly diagnosed myeloma patients, apart from supporting high dose chemotherapy, may include effects on T cell function in the bone marrow (BM). We report our exploratory findings on marrow infiltrating T cells early post-ASCT (day+100), e...

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Autores principales: Lee, Lydia, Alrasheed, Nouf, Khandelwal, Garima, Fitzsimons, Evelyn, Richards, Huw, Wilson, William, Chavda, Selina J., Henry, Jake, Conde, Lucia, De Massy, Marc Robert, Chin, Melody, Galas-Filipowicz, Daria, Herrero, Javier, Chain, Benny, Quezada, Sergio A., Yong, Kwee
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946836/
https://www.ncbi.nlm.nih.gov/pubmed/33717112
http://dx.doi.org/10.3389/fimmu.2021.618610
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author Lee, Lydia
Alrasheed, Nouf
Khandelwal, Garima
Fitzsimons, Evelyn
Richards, Huw
Wilson, William
Chavda, Selina J.
Henry, Jake
Conde, Lucia
De Massy, Marc Robert
Chin, Melody
Galas-Filipowicz, Daria
Herrero, Javier
Chain, Benny
Quezada, Sergio A.
Yong, Kwee
author_facet Lee, Lydia
Alrasheed, Nouf
Khandelwal, Garima
Fitzsimons, Evelyn
Richards, Huw
Wilson, William
Chavda, Selina J.
Henry, Jake
Conde, Lucia
De Massy, Marc Robert
Chin, Melody
Galas-Filipowicz, Daria
Herrero, Javier
Chain, Benny
Quezada, Sergio A.
Yong, Kwee
author_sort Lee, Lydia
collection PubMed
description The benefit of autologous stem cell transplantation (ASCT) in newly diagnosed myeloma patients, apart from supporting high dose chemotherapy, may include effects on T cell function in the bone marrow (BM). We report our exploratory findings on marrow infiltrating T cells early post-ASCT (day+100), examining phenotype and T cell receptor (TCR) repertoire, seeking correlations with timing of relapse. Compared to healthy donors (HD), we observed an increase in regulatory T cells (CD4+FoxP3+, Tregs) with reduction in CD4 T cells, leading to lower CD4:8 ratios. Compared to paired pre-treatment marrow, both CD4 and CD8 compartments showed a reduction in naïve, and increase in effector memory subsets, suggestive of a more differentiated phenotype. This was supported by increased levels of several immune-regulatory and activation proteins (ICOS, PD-1, LAG-3, CTLA-4 and GzmB) when compared with HD. Unsupervised analysis identified a patient subgroup with shorter PFS (p=0.031) whose BM contained increased Tregs, and higher immune-regulatory markers (ICOS, PD-1, LAG-3) on effector T cells. Using single feature analysis, higher frequencies of marrow PD-1+ on CD4+FoxP3- cells and Ki67+ on CD8 cells were independently associated with early relapse. Finally, studying paired pre-treatment and post-ASCT BM (n=5), we note reduced abundance of TCR sequences at day+100, with a greater proportion of expanded sequences indicating a more focused persistent TCR repertoire. Our findings indicate that, following induction chemotherapy and ASCT, marrow T cells demonstrate increased activation and differentiation, with TCR repertoire focusing. Pending confirmation in larger series, higher levels of immune-regulatory proteins on T cell effectors at day+100 may indicate early relapse.
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spelling pubmed-79468362021-03-12 Increased Immune-Regulatory Receptor Expression on Effector T Cells as Early Indicators of Relapse Following Autologous Stem Cell Transplantation for Multiple Myeloma Lee, Lydia Alrasheed, Nouf Khandelwal, Garima Fitzsimons, Evelyn Richards, Huw Wilson, William Chavda, Selina J. Henry, Jake Conde, Lucia De Massy, Marc Robert Chin, Melody Galas-Filipowicz, Daria Herrero, Javier Chain, Benny Quezada, Sergio A. Yong, Kwee Front Immunol Immunology The benefit of autologous stem cell transplantation (ASCT) in newly diagnosed myeloma patients, apart from supporting high dose chemotherapy, may include effects on T cell function in the bone marrow (BM). We report our exploratory findings on marrow infiltrating T cells early post-ASCT (day+100), examining phenotype and T cell receptor (TCR) repertoire, seeking correlations with timing of relapse. Compared to healthy donors (HD), we observed an increase in regulatory T cells (CD4+FoxP3+, Tregs) with reduction in CD4 T cells, leading to lower CD4:8 ratios. Compared to paired pre-treatment marrow, both CD4 and CD8 compartments showed a reduction in naïve, and increase in effector memory subsets, suggestive of a more differentiated phenotype. This was supported by increased levels of several immune-regulatory and activation proteins (ICOS, PD-1, LAG-3, CTLA-4 and GzmB) when compared with HD. Unsupervised analysis identified a patient subgroup with shorter PFS (p=0.031) whose BM contained increased Tregs, and higher immune-regulatory markers (ICOS, PD-1, LAG-3) on effector T cells. Using single feature analysis, higher frequencies of marrow PD-1+ on CD4+FoxP3- cells and Ki67+ on CD8 cells were independently associated with early relapse. Finally, studying paired pre-treatment and post-ASCT BM (n=5), we note reduced abundance of TCR sequences at day+100, with a greater proportion of expanded sequences indicating a more focused persistent TCR repertoire. Our findings indicate that, following induction chemotherapy and ASCT, marrow T cells demonstrate increased activation and differentiation, with TCR repertoire focusing. Pending confirmation in larger series, higher levels of immune-regulatory proteins on T cell effectors at day+100 may indicate early relapse. Frontiers Media S.A. 2021-02-25 /pmc/articles/PMC7946836/ /pubmed/33717112 http://dx.doi.org/10.3389/fimmu.2021.618610 Text en Copyright © 2021 Lee, Alrasheed, Khandelwal, Fitzsimons, Richards, Wilson, Chavda, Henry, Conde, De Massy, Chin, Galas-Filipowicz, Herrero, Chain, Quezada and Yong 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
Lee, Lydia
Alrasheed, Nouf
Khandelwal, Garima
Fitzsimons, Evelyn
Richards, Huw
Wilson, William
Chavda, Selina J.
Henry, Jake
Conde, Lucia
De Massy, Marc Robert
Chin, Melody
Galas-Filipowicz, Daria
Herrero, Javier
Chain, Benny
Quezada, Sergio A.
Yong, Kwee
Increased Immune-Regulatory Receptor Expression on Effector T Cells as Early Indicators of Relapse Following Autologous Stem Cell Transplantation for Multiple Myeloma
title Increased Immune-Regulatory Receptor Expression on Effector T Cells as Early Indicators of Relapse Following Autologous Stem Cell Transplantation for Multiple Myeloma
title_full Increased Immune-Regulatory Receptor Expression on Effector T Cells as Early Indicators of Relapse Following Autologous Stem Cell Transplantation for Multiple Myeloma
title_fullStr Increased Immune-Regulatory Receptor Expression on Effector T Cells as Early Indicators of Relapse Following Autologous Stem Cell Transplantation for Multiple Myeloma
title_full_unstemmed Increased Immune-Regulatory Receptor Expression on Effector T Cells as Early Indicators of Relapse Following Autologous Stem Cell Transplantation for Multiple Myeloma
title_short Increased Immune-Regulatory Receptor Expression on Effector T Cells as Early Indicators of Relapse Following Autologous Stem Cell Transplantation for Multiple Myeloma
title_sort increased immune-regulatory receptor expression on effector t cells as early indicators of relapse following autologous stem cell transplantation for multiple myeloma
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946836/
https://www.ncbi.nlm.nih.gov/pubmed/33717112
http://dx.doi.org/10.3389/fimmu.2021.618610
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