Inactivation of beta-2 microglobulin (B2M) is considered a determinant of resistance to immune checkpoint inhibitors (ICPi) in melanoma and lung cancers. In contrast,
loss does not appear to affect ...response to ICPis in mismatch repair-deficient (MMRd) colorectal tumors where biallelic inactivation of
is frequently observed. We inactivated
in multiple murine MMRd cancer models. Although MMRd cells would not readily grow in immunocompetent mice, MMRd
null cells were tumorigenic and regressed when treated with anti-PD-1 and anti-CTLA4. The efficacy of ICPis against MMRd
null tumors did not require CD8
T cells but relied on the presence of CD4
T cells. Human tumors expressing low levels of B2M display increased intratumoral CD4
T cells. We conclude that B2M inactivation does not blunt the efficacy of ICPi in MMRd tumors, and we identify a unique role for CD4
T cells in tumor rejection. SIGNIFICANCE:
alterations, which impair antigen presentation, occur frequently in microsatellite-unstable colorectal cancers. Although in melanoma and lung cancers
loss is a mechanism of resistance to immune checkpoint blockade, we show that MMRd tumors respond to ICPis through CD4
T-cell activation.
.
The Sin3 transcriptional regulator homolog A (Sin3A) is the core member of a multiprotein chromatin‐modifying complex. Its inactivation at the CD4/CD8 double‐negative stage halts further thymocyte ...development. Among various functions, Sin3A regulates STAT3 transcriptional activity, central to the differentiation of Th17 cells active in inflammatory disorders and opportunistic infections. To further investigate the consequences of conditional Sin3A inactivation in more mature precursors and post‐thymic T cell, we have generated CD4‐Cre and CD4‐CreERT2 Sin3AF/F mice. Sin3A inactivation in vivo hinders both thymocyte development and peripheral T‐cell survival. In vitro, in Th17 skewing conditions, Sin3A‐deficient cells proliferate and acquire memory markers and yet fail to properly upregulate Il17a, Il23r, and Il22. Instead, IL‐2+ and FOXP3+ are mostly enriched for, and their inhibition partially rescues IL‐17A+ T cells. Notably, Sin3A deletion also causes an enrichment of genes implicated in the mTORC1 signaling pathway, overt STAT3 activation, and aberrant cytoplasmic RORγt accumulation. Thus, together our data unveil a previously unappreciated role for Sin3A in shaping critical signaling events central to the acquisition of immunoregulatory T‐cell phenotypes.
Synopsis
This study identifies a role for the transcriptional regulator Sin3A in shaping Th‐17 differentiation. Inducible Sin3A deletion causes overt STAT3 activation and aberrant cytoplasmic RORγt localization hindering IL‐17A levels in favor of Foxp3 expression.
The transcriptional regulator Sin3A contributes to CD4 T‐cell development and differentiation.
Sin3A inactivation in mature T cells promotes mTORC1 signaling, STAT3 activation, and aberrant cytoplasmic RORγt accumulation.
Sin3A balances IL‐17A, IL‐2, and Foxp3, thereby shaping the immunoregulatory potential of Th17 lymphocytes.
This study identifies a role for the transcriptional regulator Sin3A in shaping Th‐17 differentiation. Inducible Sin3A deletion causes overt STAT3 activation and aberrant cytoplasmic RORγt localization hindering IL‐17A levels in favor of Foxp3 expression.
Eosinophilia is common in childhood, and in most cases it is mild and of limited clinical relevance, being often secondary to allergy or infections. In rare cases, eosinophilia may be idiopathic or ...related to neoplastic aetiology. When severe and protracted, it can cause potentially irreversible organ or system damage, whose prevention is the first priority in the clinical management of hypereosinophilia. We describe the case of a patient with very severe eosinophilia, in whom antihistamines proved to be effective and safe in contributing to the eosinophil count normalization, thus avoiding the use of steroids until the hypothesis of an underlying neoplastic disorder was reasonably excluded.
to assess the effect of topical administration of the Neurokin-1 receptor (NK1R) antagonist Fosaprepitant in a pre-clinical model of ocular Graft-versus-Host disease (GVHD).
BALB/c mice were ...pre-conditioned by myeloablative total body irradiation and subjected to allogeneic bone marrow transplantation and mature T cell infusion (BM + T). BM-transplanted mice (BM) were used as controls. Ocular GVHD was specifically assessed by quantifying corneal epithelial damage, tear secretion, blepharitis and phimosis, 3 times/week for 28 days post-transplantation. A group of BM + T mice received Fosaprepitant 10 mg/mL, 6 times/day, topically, from day 7–29 after transplantation. After sacrifice, the expression of NK1R, CD45, CD3, and CXCL10 was quantified in the cornea, conjunctiva, and lacrimal gland by immunohistochemistry.
BM + T mice developed corneal epithelial damage (day 0–29, p < 0.001), blepharitis (day 0–29, p < 0.001), and phimosis (day 0–29, p < 0.01), and experienced decreased tear secretion (day 21, p < 0.01) compared to controls. NK1R was found upregulated in corneal epithelium (p < 0.01) and lacrimal gland (p < 0.01) of BM + T mice. Fosaprepitant administration significantly reduced corneal epithelial damage (p < 0.05), CD45+ (p < 0.05) and CD3+ (p < 0.01) immune cell infiltration in the cornea and conjunctiva (p < 0.001 and p < 0.001, respectively). In addition, Fosaprepitant reduced the expression of CXCL10 in the cornea (p < 0.05) and in the lacrimal gland (p < 0.05).
Our results suggest that NK1R represents a novel druggable pathway for the therapy of ocular GVHD.
•Ocular GVHD is characterized by corneal epithelial disease, blepharitis, and phimosis.•The expression of NK1R increases in the cornea and lacrimal gland in GVHD.•Topical NK1R antagonist ameliorates inflammation and clinical signs of ocular GVHD.•NK1R represents a novel druggable pathway for the therapy of ocular GVHD.
Summary
Mycophenolate mofetil (MMF) has been shown to be effective in children with immune thrombocytopenia (ITP) and Evans syndrome (ES), but data from larger series and details on the timing of the ...response are lacking. We evaluated 56 children treated with MMF for ITP (n = 40) or ES (n = 16), which was primary or secondary to autoimmune lymphoproliferative syndrome ‐related syndrome (ARS). Thirty‐five of the 54 evaluable patients (65%) achieved a partial (18%) or complete (46%) response after a median (range) of 20 (7–137) and 37 (7–192) d, respectively. ITP and ES patients responded in 58% and 81% of cases (P = not significant, ns), with complete response in 32% and 81% (P = 0·01), respectively. 60% and 73% of children with primary disease and ARS responded (P = ns) with complete response in 34% and 68% of cases (P = 0·01), respectively. Six of 35 (17%) children relapsed after a median of 283 d (range 189–1036). Limited toxicity was observed in four patients. The median durations of treatment and follow‐up were seven and 12·7 months, respectively. This is the largest reported cohort of patients treated with MMF for ITP/ES. The results show that MMF is effective and safe and provides a relatively quick response, suggesting that it has a potential role as an alternative to more aggressive and expensive second/further‐line treatments.
Background: Identifying perioperative bleeding risk in pediatric patients undergoing major surgery is challenging because personal history is often not sufficiently informative and laboratory tests ...are also more susceptible to pre-analytical variables. Children with low Willebrand add further uncertainty in the treatment options. The aim of this study was to evaluate practices to assess hemorrhagic risk and manage bleeding prophylaxis in children with low von Willebrand factor levels (30 and 50 IU/dL; low VWF), known von Willebrand disease (VWD) or healthy controls undergoing ear, nose and throat (ENT) surgery. Methods: In this retrospective observational study, data from consecutive paediatric patients undergoing ENT surgery between January 1, 2010 and December 31, 2017 at the Turin Paediatric Hospital were analysed. All statistical analyses were performed using STATA (StataCorp. 2013. Been Statistical Software: Release 13. College Station, TX: StataCorp LP). Demographic and clinical characteristics of patients were assessed using the absolute frequencies and percentages for qualitative variables and percentiles for quantitative variables. The risk of bleeding was estimated from the number of patients who experienced bleeding within 21 days as a proportion of the number of patients subjected to surgery. 90% confidence intervals (90% CIs) were estimated for the evaluation of bleeding risk, using the Jeffreys method and any differences in the risk of bleeding between patient groups were tested using a proportions test. To investigate any factors associated with the therapeutic strategy used, multinomial logistic regression models were conducted. Results: Major perioperative bleeding was seen in 6.3% (5/79) of low VWF patients, 3.0% (35/1152) of healthy controls and 20.0% (5/25) of patients with VWD. In low VWF patients, perioperative bleeding prophylaxis was given to 59.5% and included subcutaneously desmopressin (n=21) and VWF-containing concentrate (n=26). Oral or intravenous tranexamic acid was administered to all low VWF patients. Of these patients, one major hemorrhagic event occurred in patients who did not receive prophylaxis and the remaining events occurred in patients treated with VWF-containing concentrate. In patients who received a VWF-containing concentrate, lower VWF ristocetin cofactor levels were observed compared with patients who received desmopressin or were untreated during surgery. No differences in clinical and laboratory features were observed between patients with low VWF treated with desmopressin and those who were untreated. Conclusions: Patients with low VWF have a higher risk of perioperative bleeding compared with healthy controls but a significantly lower risk compared with patients with VWD. The perioperative management of these patients is complex with a high risk of overtreatment. In our experience the caution of keeping the VWF-containing concentrate in the operating room available for use in case of bleeding appears to be a balanced approach. Prospective randomized studies to identify accurate methods of assessing bleeding risk and evaluate the most effective perioperative bleeding prevention are warranted.
Essential bibliography:
Ruchika Sharma and Veronica H. Flood. Advances in the diagnosis and treatment of Von Willebrand disease. Hematology American Society of Hematology Education Program 2017:379-384
Sadler JE. Low von Willebrand factor: sometimes a risk factor and sometimes a disease. Hematology American Society of Hematology Education Program 2009:106-112
Rodeghiero F, Tosetto A, Abshire T, et al. ISTH/SSC bleeding assessment tool: a standardized questionnaire and a proposal for a new bleeding score for inherited bleeding disorders. J Thromb Haemost. 2010;8(9):2063-2065.
Casey LJ, Tuttle A, Grabell J, et al. Generation and optimization of the self-administered pediatric bleeding questionnaire and its validation as a screening tool for von Willebrand disease. Pediatr Blood Cancer. 2017;64(10)
Mannuccio Mannucci P, Kyrle PA, Schulman S, Di Paola J, Schneppenheim R, Cox Gill J. Prophylactic efficacy and pharmacokinetically guided dosing of a von Willebrand factor/factor VIII concentrate in adults and children with von Willebrand's disease undergoing elective surgery: a pooled and comparative analysis of data from USA and European Union clinical trials. Blood Transfus. 2013;11(4):533-540
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No relevant conflicts of interest to declare.
The phenotype of infused cells is a major determinant of Adoptive T‐cell therapy (ACT) efficacy. Yet, the difficulty in deciphering multiparametric cytometry data limited the fine characterization of ...cellular products. To allow the analysis of dynamic and complex flow cytometry samples, we developed cytoChain, a novel dataset mining tool and a new analytical workflow. CytoChain was challenged to compare state‐of‐the‐art and innovative culture conditions to generate stem‐like memory cells (TSCM) suitable for ACT. Noticeably, the combination of IL‐7/15 and superoxides scavenging sustained the emergence of a previously unidentified nonexhausted Fit‐TSCM signature, overlooked by manual gating and endowed with superior expansion potential. CytoChain proficiently traced back this population in independent datasets, and in T‐cell receptor engineered lymphocytes. CytoChain flexibility and function were then further validated on a published dataset from circulating T cells in COVID‐19 patients. Collectively, our results support the use of cytoChain to identify novel, functionally critical immunophenotypes for ACT and patients immunomonitoring.
Exploring TCR‐engineered T cells interactions with cytoChain entails superior data mining. CytoChain is a novel workflow and application able to underline qualitative differences missed by both manual gating or canonical high‐dimensional analysis. Its utilization underlined the effects of various supplements upon T‐cell Receptor gene editing, and the T cell changes developing in COVID‐19 patients according to disease severity.
Abstract Several events control the activation, proliferation, and the continued Ag responsiveness of naïve and memory T lymphocytes. Here we review the individual contributions of TCR, CD28, and ...IL-2-driven signaling to T cell proliferation and anergy avoidance. The role of mTOR as a rheostat capable of integrating extracellular, plasma membrane-associated, and intracellular signals with relevance to T cell priming and tolerance is discussed.
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