Lower BCL11B expression is associated with adverse clinical outcome for patients with myelodysplastic syndrome

AbstractMyelodysplastic syndrome (MDS) is an aggressive and genetically heterogeneous disease with poor prognosis. Cellular immune disorder is a common characteristic of this disease and is thought to be related to clinical outcome. Alterations in T cell clonal expansion and T cell dysfunction has been detected in MDS patients. Little is known about whether there are immune biomarkers to evaluate the T cell alterations with clinical outcome. Previous studies have demonstrated that B-cell leukemia/lymphoma 11B (BCL11B) plays an important role in regulating T cell development and proliferation. In this study, the prognostic value of BCL11B for MDS patients was explored by analyzing RNA-seq data from 270 patients in two datasets in the Gene Expression Omnibus (GEO) database and real-time quantitative PCR data (qRT-PCR) of 31 bone marrow (BM) samples of MDS and 6 BM samples of patients with MDS progress to secondary acute myeloid leukemia (sAML) from our clinical center. The results demonstrated that BCL11B is significantly down-regulated in MDS patients as compared with healthy individuals (HIs). Importantly, lower BCL11B expression was found in MDS patients who were of high/very high risk, older than 60 y, or male and patients with sAML. Furthermore, low BCL11B expression appeared to be associated with poor overall survival (OS) for MDS patients, though the data were not yet significant enough at this point. In addition, BCL11B low-expressing MDS patients had shorter restricted mean survival time (RMST) than those with high BCL11B expression. Interestingly, BCL11B positively correlated with naive and activated memory CD4 + T cells, CD8 + T cells, and the T cell receptor complex genes CD3E and CD3G, but it negatively correlated with regulatory T cells (Treg). Additionally, co-occurrence of low BCL11B expression and CD3E and CD3G was associated with poor OS and shorter RMST. In conclusion, lower BCL11B expression in BM samples of MDS patients was associated with adverse clinical outcome.

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Checkpoint-blocker induced autoimmunity is associated with pretreatment T cell expression profiles and favourable outcome in melanoma

10.1101/2020.06.23.20138594 ◽

2020 ◽

Author(s):

W. Ye ◽

A Olsson-Brown ◽

R. A. Watson ◽

V. T. F. Cheung ◽

R. D. Morgan ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Clinical Outcome ◽

Adverse Events ◽

Metastatic Melanoma ◽

T Cell Receptor ◽

Immune Checkpoint ◽

Single Agent ◽

Cell Receptor ◽

Pre Treatment

1Abstract1.1BackgroundImmune checkpoint blockers (ICBs) activate CD8+ T cells to elicit anti-cancer activity but frequently lead to immune-related adverse events (irAEs). The relationship of irAE with baseline parameters and clinical outcome is unclear. We investigated associations between irAE development, CD8+ T cell receptor diversity and expression and clinical outcome in a non-trial setting.1.2MethodsPatients ≥18 years old with metastatic melanoma (MM) receiving combination ICB (ipilimumab plus nivolumab – cICB, n=60) or single-agent ICB (nivolumab/pembrolizumab – sICB, n=78) were prospectively recruited. We retrospectively evaluated the impact of irAEs on survival. This analysis was repeated in an independent cohort of MM patients treated at a separate institution (n=210, cICB:74, sICB:136). We performed RNA sequencing of CD8+ T cells isolated from patients prior to treatment, analysing T cell receptor clonality differential transcript expression according to irAE development.1.3Results48.6% of patients experienced treatment-related irAEs within the first 5 cycles of treatment. Development of irAE prior to the 5th cycle of ICB was associated with longer progression-free and overall survival (PFS, OS) in the primary cohort (log-rank test, PFS: P=0.00034; OS: P<0.0001), replicated in the secondary cohort (OS: P=0.00064). Across cohorts median survival for those patients not experiencing irAE was 14.4 (95% CI:9.6-19.5) months vs not-reached (95% CI:28.9 - Inf), P=3.0×10−7. Pre-treatment performance status and neutrophil count, but not BMI, were additional predictors of clinical outcome. Analysis of CD8+ T cells from 128 patients demonstrated irAE development was associated with increased T cell receptor diversity post-treatment (P=4.3×10−5). Development of irAE in sICB recipients was additionally associated with baseline differential expression of 224 transcripts (FDR<0.1), enriched in pro-inflammatory pathway genes including CYP4F3 and PTGS2.1.4ConclusionsEarly irAE development post-ICB is strongly associated with favourable survival in MM and increased diversity of peripheral CD8+ T cell receptors after treatment. irAE post-sICB is associated with pre-treatment upregulation of inflammatory pathways, indicating irAE development may reflect baseline immune activation states.Key messageImmune-related adverse events (irAEs) commonly occur in patients with metastatic melanoma treated with immune checkpoint blockade (ICB) therapy. In real world setting we find development of early irAEs post-ICB treatment is associated with survival benefit, indicative of a shared mechanism with anti-tumour efficacy. CD8+ T cells from patients who develop irAE show increased receptor diversity, and pre-treatment samples from patients who develop irAE post single-agent anti-PD1 show over-expression of inflammatory pathways, indicating baseline immune state can determine irAE development.

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Defective Vav expression and impaired F-actin reorganization in a subset of patients with common variable immunodeficiency characterized by T-cell defects

Blood ◽

10.1182/blood-2004-05-2051 ◽

2005 ◽

Vol 106 (2) ◽

pp. 626-634 ◽

Cited By ~ 48

Author(s):

Silvia Rossi Paccani ◽

Marianna Boncristiano ◽

Laura Patrussi ◽

Cristina Ulivieri ◽

Andreas Wack ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Common Variable Immunodeficiency ◽

Cell Function ◽

Cell Receptor ◽

Actin Dynamics ◽

Mrna Levels ◽

Immune Disorder ◽

Actin Reorganization ◽

Common Variable

Abstract Common variable immunodeficiency (CVID) is a primary immune disorder characterized by impaired antibody production, which is in many instances secondary to defective T-cell function (T-CVID). We have previously identified a subset of patients with T-CVID characterized by defective T-cell receptor (TCR)-dependent protein tyrosine phosphorylation. In these patients, ZAP-70 fails to be recruited to the TCR as the result of impaired CD3ζ phosphorylation, which is, however, not dependent on defective Lck expression or activity. Here we show that neither Fyn nor CD45 is affected in these patients. On the other hand, T-CVID T cells show dramatic defects in the Vav/Rac pathway controlling F-actin dynamics. A significant deficiency in Vav protein was indeed observed; in 3 of 4 patients with T-CVID, it was associated with reduced VAV1 mRNA levels. The impairment in Vav expression correlated with defective F-actin reorganization in response to TCR/CD28 coengagement. Furthermore, TCR/CD28-dependent up-regulation of lipid rafts at the cell surface, which requires F-actin dynamics, was impaired in these patients. The actin cytoskeleton defect could be reversed by reconstitution of Vav1 expression in the patients' T cells. Results demonstrate an essential role of Vav in human T cells and strongly suggest Vav insufficiency in T-CVID. (Blood. 2005;106:626-634)

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