FOXP3 and helios expressing CD4+ T conventional cells are a regulatory-like subset that is induced after orca-T allogeneic immunotherapy
Notice bibliographique
Résumé
Abstract Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative therapy for many hematologic malignancies. The primary non-relapse complication preventing the widespread use of allo-HSCT is graft-versus-host disease (GVHD). The use of T regulatory cells (Tregs) to prevent GVHD has emerged as a promising allogeneic T cell immunotherapy in the form of Orca-T. Orca-T consists of the sequential infusion of CD34+ hematopoietic stem cells and high-purity Tregs followed by conventional T cells. However, the precise differences in immune states which may influence clinical outcomes after Orca-T compared with unmanipulated peripheral blood stem cell (PBSC) grafts remains unexplored. Using peripheral blood specimens longitudinally collected between 3 weeks and 1 year after leukemia treatment, we report single-cell mRNA sequencing (scRNA-seq) and flow cytometric analysis of 51 HLA-matched patients receiving either Orca-T or unmanipulated PBSC grafts at Stanford University. To identify potentially important T cell populations that drive clinical differences between Orca-T and unmanipulated PBSC grafts, sorted T cell subsets or whole PBMC from 16 total patients were captured for scRNA-seq analysis 3 weeks post-treatment. Targeted transcriptomic and V(D)J analysis identified increased expression of FOXP3 and Helios amongst CD4+CD25- T conventional cells (Tcons) in Orca-T treated patients (7.8% Orca-T vs. 3.0% PBSC, p=0.035). Moreover, in Orca-T recipients, there was a trend towards a higher proportion of expanding clones (≥2 identical clones) which belonged to the CD4+CD25-FOXP3+Helios+ cluster than in PBSC graft recipients (14.7% vs. 2.3%, p=0.095). Separate single-cell whole transcriptome analysis also found increased expression of FOXP3 and Helios amongst activated CD4+ Tcons from Orca-T recipients compared to PBSC graft recipients. Flow cytometric analysis of 20 additional patients corroborated the increased frequency of CD4+FOXP3+Helios+ Tcons - but not Tregs – 3 weeks post-treatment in patients receiving Orca-T (11.6% Orca-T vs. 4.4% PBSC, p=0.016). Further, we discovered that this T cell subset correlated significantly with frequencies of HLA-DR+ and effector memory CD4+ T cells (p=0.002, p=0.032) and effector memory CD8+ T cells (p=0.014) 3 months post-treatment, regardless of which therapy patients received. These data suggest that Orca-T immunotherapy induces a FOXP3+Helios+ Tcon population which may play a role in long-term immune reconstitution after allo-HSCT. Next, we confirmed the increased frequency of CD4+CD25-FOXP3+Helios+ T cells early after Orca-T immunotherapy in a second cohort of 19 cryopreserved patient samples collected 2 weeks after treatment, including 12 which were transplanted at other centers (11.7% Orca-T vs. 4.3% PBSC, p=0.029). In contrast, a comparative examination of 14 mobilized donor PBMC samples found that only 1% of donor Tcons expressed FOXP3 and Helios (p=<0.0001 vs. Orca-T, p=0.23 vs. PBSC). In week +2 recipient samples that were matched to mobilized donor PBMC, we found an average 10.3-fold increase (p=0.011) in CD4+CD25-FOXP3+Helios+ cell frequency in Orca-T recipients compared to their donor. In contrast, PBSC recipients exhibited a 5.9-fold increase (p=0.023), suggesting that Orca-T immunotherapy greatly promotes the in vivo expansion or differentiation of these cells compared to standard PBSC grafts. We also identified that CD4+CD25-FOXP3+Helios+ T cells were phenotypically similar in donors, Orca-T recipients, and PBSC recipients, indicating a common expression profile regardless of overall immune state. Compared to other CD4+ Tcons and Tregs, CD4+CD25-FOXP3+Helios+ T cells represented a unique T cell subset with intermediate expression of immunomodulatory proteins including CD39, CTLA-4, HLA-DR, TIGIT, and the distribution of naïve and effector memory cells (ANOVA p=<0.0001 for each) along with distinct expression of CD73 (ANOVA p=0.007). We therefore propose that CD4+CD25-FOXP3+Helios+ cells are a regulatory-like subset of T cells which are induced by Orca-T immunotherapy and that this population contributes to GVHD suppression in concert with other regulatory populations after leukemia treatment. Overall, we hypothesize that the sequential addition of high-purity Tregs directs the immune reconstitution of CD4+CD25- Tcons towards a non-redundant, immunomodulatory, FOXP3+Helios+ phenotype which may be predictive of long-term immune activation after T cell infusion.
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Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».