Frontiers in Immunology (2021-02-01)

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

  • Lydia Lee,
  • Nouf Alrasheed,
  • Garima Khandelwal,
  • Evelyn Fitzsimons,
  • Huw Richards,
  • William Wilson,
  • Selina J. Chavda,
  • Jake Henry,
  • Jake Henry,
  • Lucia Conde,
  • Marc Robert De Massy,
  • Marc Robert De Massy,
  • Marc Robert De Massy,
  • Melody Chin,
  • Daria Galas-Filipowicz,
  • Javier Herrero,
  • Benny Chain,
  • Sergio A. Quezada,
  • Sergio A. Quezada,
  • Kwee Yong

DOI
https://doi.org/10.3389/fimmu.2021.618610
Journal volume & issue
Vol. 12

Abstract

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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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