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Clonal expansion of CD8+ T cells reflects graft-versus-leukemia activity and precedes durable remission following DLI.

ABSTRACT: Donor lymphocyte infusion (DLI) is a standard of care for relapse of AML after allogeneic hematopoietic stem cell transplantation (aHSCT). Currently it is poorly understood how and when CD8+ αβ T cells exert graft-versus-leukemia (GvL) activity after DLI. Also, there is no reliable biomarker to monitor GvL activity of the infused CD8+ T cells. Therefore, we analyzed the dynamics of CD8+ αβ T cell clones in DLI-patients. In this prospective clinical study of 29 patients, we performed deep T cell receptor β (TRB) sequencing of sorted CD8+ αβ T cells to track patients' repertoire changes in response to DLI. Upon first occurrence of GvL, longitudinal analyses revealed a preferential expansion of distinct CD8+ TRB clones (n=14). This did not occur in samples of patients without signs of GvL (n=11). Importantly, early repertoire changes 15 days after DLI predicted durable remission for the 36 months study follow-up. Furthermore, absence of clonal outgrowth of the CD8+ TRB repertoire after DLI was an early biomarker that predicted relapse at a median time of 11.2 months ahead of actual diagnosis. Additionally, unbiased sample analysis regardless of the clinical outcome revealed that patients with decreasing CD8+ TRB diversity at day 15 after DLI (n=13) had a lower relapse incidence (P=0.0040) compared to patients without clonal expansion (n=6). In conclusion, CD8+ TRB analysis may provide a reliable tool for predicting the efficacy of DLI and holds the potential to identify patients at risk for progression and relapse after DLI.

SUBMITTER: Schultze-Florey CR

PROVIDER: S-EPMC8579265 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Clonal expansion of CD8+ T cells reflects graft-versus-leukemia activity and precedes durable remission following DLI.

Project description:We show that an effective GvL is associated with a substantial drop of CD8+ TRB diversity and a concomitant expansion of dominant clones.

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Clonal expansion of CD8+ T cells reflects graft-versus-leukemia activity and precedes durable remission following DLI.

Project description:Clonal expansion of CD8+ T cells reflects graft-versus-leukemia activity and precedes durable remission following DLI.

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Clonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia.

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Lymphodepletion followed by donor lymphocyte infusion (DLI) causes significantly more acute graft-versus-host disease than DLI alone.

Project description:Donor lymphocyte infusions (DLIs) can produce lasting remissions in patients with relapsed chronic myeloid leukemia (CML), but are less effective in non-CML diseases. We hypothesized that lymphodepletion, achieved with cyclophosphamide (Cy) and fludarabine (Flu), would promote in vivo expansion of the infused lymphocytes enhancing their immunologic effects. Fifteen patients with relapsed non-CML disease who received Cy/Flu/DLI were compared with 63 controls who received DLI without chemotherapy. Only the patients receiving Cy/Flu/DLI became lymphopenic at the time of DLI. Compared with controls, patients who received Cy/Flu/DLI developed significantly more grades II to IV (60% vs 24%, P = .01) and grades III to IV acute graft-versus-host disease (GVHD) (47% vs 14%, P = .01) with greater GVHD lethality. In Cy/Flu/DLI patients, T-cell proliferation was elevated at 14 days after DLI. Although these data suggest that chemotherapy-induced lymphodepletion enhances activation of donor lymphocytes, the toxicity needs to be managed before testing whether better disease control can be achieved. This trial was registered at www.clinicaltrials.gov as no. NCT00303693 and www.cancer.gov/clinicaltrials as no. NCT00167180.

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Clonal expansion of bone marrow CD8<sup>+</sup> T cells in acute myeloid leukemia patients at new diagnosis and after chemotherapy.

Project description:CD8+ T cells are crucial adaptive immune effectors and express receptors (T cell receptors, TCRs) that specifically recognize and eradicate tumor cells. The diversity of the TCR repertoire is generated by specialized genetic diversification mechanisms, which lead to an extremely variable TCR repertoire that is capable of recognizing a wide range of antigens. However, the variations in CD8+ TCR diversity and their clinical implications in acute myeloid leukemia (AML) patients remain unknown. CD8+ T cells were enriched from 10 healthy donors and 31 AML patients at diagnosis and after chemotherapy, and TCRβ deep sequencing was performed to analyze CD8+ T cell clonal expansion and TCR repertoire diversity. Diminished TCR repertoire diversity and increased T cell clone expansion were noted in the bone marrow of AML patients. In relapsed patients, T cells were found to be more clonally expanded after chemotherapy than at new diagnosis. Moreover, significantly more expanded TCRβ clonotypes were noted in CD8+ PD-1+ T cells than in CD8+ PD-1- T cells regardless of the time of examination. Our systematic T cell repertoire analysis may help better characterize CD8+ T cells before and after chemotherapy in AML, which may provide insights into therapeutic strategies for hematological malignancies.

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Select sequencing of clonally expanded CD8+ T cells reveals limits to clonal expansion.

Project description:To permit the recognition of antigens, T cells generate a vast diversity of T cell receptor (TCR) sequences. Upon binding of the TCR to an antigen-MHC complex, T cells clonally expand to establish an immune response. To study antigen-specific T cell clonality, we have developed a method that allows selection of rare cells, based on RNA expression, before in-depth scRNA-seq (named SELECT-seq). We applied SELECT-seq to collect both TCR sequences and then transcriptomes from single cells of peripheral blood lymphocytes activated by a Mycobacterium tuberculosis (Mtb) lysate. TCR sequence analysis allowed us to preferentially select expanded conventional CD8+ T cells as well as invariant natural killer T (iNKT) cells and mucosal-associated invariant T (MAIT) cells. The iNKT and MAIT cells have a highly similar transcriptional pattern, indicating that they carry out similar immunological functions and differ considerably from conventional CD8+ T cells. While there is no relationship between expression profiles and clonal expansion in iNKT or MAIT cells, highly expanded conventional CD8+ T cells down-regulate the interleukin 2 (IL-2) receptor alpha (IL2RA, or CD25) protein and show signs of senescence. This suggests inherent limits to clonal expansion that act to diversify the T cell response repertoire.

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SLAT regulates CD8+ T cell clonal expansion in a Cdc42- and NFAT1-dependent manner.

Project description:After antigenic stimulation, CD8(+) T cells undergo clonal expansion and differentiation into CTLs that can mount a strong defense against intracellular pathogens and tumors. SWAP-70-like adapter of T cells (SLAT), also known as Def6, is a novel guanine nucleotide exchange factor for the Cdc42 GTPase and plays a role in CD4(+) T cell activation and Th cell differentiation by controlling Ca(2+)/NFAT signaling, but its requirement in CD8(+) T cell response has not been explored. Using a range of transgenic and knockout in vivo systems, we show that SLAT is required for efficient expansion of CD8(+) T cells during the primary response but is not necessary for CTL differentiation. The reduced clonal expansion observed in the absence of SLAT resulted from a CD8(+) T cell-intrinsic proliferation defect and a reduced IL-2-dependent cell survival. On a molecular level, we show that Def6 deficiency resulted in defective TCR/CD28-induced NFAT translocation to the nucleus in CD8(+) T cells. Constitutively active Cdc42 or NFAT1 mutants fully restored the impaired expansion of Def6(-/-) CD8(+) T cells. Taken together, these data describe a new and pivotal role of SLAT-mediated NFAT activation in CD8(+) T cells, providing new insight into the signaling pathways involved in CD8(+) T cell proliferation.

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