Abstract
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.
Highlights
Current standard of care in young fit patients with newly diagnosed multiple myeloma (MM) is several cycles of induction chemotherapy followed by high dose melphalan and autologous stem cell transplantation (ASCT) [1,2,3]
T regulatory cells (Tregs) cells are generally increased in MM patients compared with healthy donors (HD), whether at diagnosis or post-ASCT
With respect to clinical outcomes, we used unsupervised analysis to identify a patient subgroup at greater risk of early relapse (p=0.031) whose bone marrow (BM) contained higher frequencies of Tregs, and greater co-activation and co-inhibitory marker (ICOS, progressive disease (PD)-1, LAG-3) expression on Tregs, CD4eff, and CD8 cells
Summary
Current standard of care in young fit patients with newly diagnosed multiple myeloma (MM) is several cycles of induction chemotherapy followed by high dose melphalan and autologous stem cell transplantation (ASCT) [1,2,3]. While high dose therapy eradicates residual tumor cells, an increasing body of evidence suggests that immunological mechanisms may contribute to the prolongation of disease-free survival following ASCT. The expansion of T cell clones post-ASCT and early lymphocyte recovery has been associated with longer PFS, suggesting that early immune reconstitution is important in controlling disease progression in MM patients [5,6,7,8]. MM patients suffering early relapse post-ASCT were observed to have an increased frequency of exhausted or senescent T cells [9]. The immune “fitness” of the reconstituting marrow cells may influence clinical outcomes in patients receiving ASCT
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