NOTCH Signaling in T-Cell-Mediated Anti-Tumor Immunity and T-Cell-Based Immunotherapies

The NOTCH (1–4) family of receptors are highly conserved and are critical in regulating many developmental processes and in the maintenance of tissue homeostasis. Our laboratory and numerous others have demonstrated that aberrant NOTCH signaling is oncogenic in several different cancer types. Conversely, there is also evidence that NOTCH can also function as a tumor suppressor. In addition to playing an essential role in tumor development, NOTCH receptors regulate T-cell development, maintenance, and activation. Recent studies have determined that NOTCH signaling is required for optimal T-cell-mediated anti-tumor immunity. Consequently, tumor cells and the tumor microenvironment have acquired mechanisms to suppress NOTCH signaling to evade T-cell-mediated killing. Tumor-mediated suppression of NOTCH signaling in T-cells can be overcome by systemic administration of NOTCH agonistic antibodies and ligands or proteasome inhibitors, resulting in sustained NOTCH signaling and T-cell activation. In addition, NOTCH receptors and ligands are being utilized to improve the generation and specificity of T-cells for adoptive transplant immunotherapies. In this review, we will summarize the role(s) of NOTCH signaling in T-cell anti-tumor immunity as well as TCR- and chimeric antigen receptor-based immunotherapies

Fanconi-BRCA pathway mutations in childhood T-cell acute lymphoblastic leukemia

BRCA2 (also known as FANCD1) is a core component of the Fanconi pathway and suppresses transformation of immature T-cells in mice. However, the contribution of Fanconi-BRCA pathway deficiency to human T-cell acute lymphoblastic leukemia (T-ALL) remains undefined. We identified point mutations in 9 (23%) of 40 human T-ALL cases analyzed, with variant allele fractions consistent with heterozygous mutations early in tumor evolution. Two of these mutations were present in remission bone marrow specimens, suggesting germline alterations. BRCA2 was the most commonly mutated gene. The identified Fanconi-BRCA mutations encode hypomorphic or null alleles, as evidenced by their inability to fully rescue Fanconi-deficient cells from chromosome breakage, cytotoxicity and/or G2/M arrest upon treatment with DNA cross-linking agents. Disabling the tumor suppressor activity of the Fanconi-BRCA pathway is generally thought to require biallelic gene mutations. However, all mutations identified were monoallelic, and most cases appeared to retain expression of the wild-type allele. Using isogenic T-ALL cells, we found that BRCA2 haploinsufficiency induces selective hypersensitivity to ATR inhibition, in vitro and in vivo. These findings implicate Fanconi-BRCA pathway haploinsufficiency in the molecular pathogenesis of T-ALL, and provide a therapeutic rationale for inhibition of ATR or other druggable effectors of homologous recombination

Resident Education in the Time of a Global Pandemic: Development of the Collaborative OMS Virtual Interinstitutional Didactic (COVID) Program

Disparity in didactic education among oral and maxillofacial surgery (OMS) training programs has driven a national conversation regarding the need for a standardized OMS curriculum, which has been recently amplified by the drastic interruption of OMS training programs during the coronavirus disease 2019 (COVID-19) pandemic. In the present report, we have described the Collaborative OMS Virtual Inter-institutional Didactic (COVID) Program, a multi-institutional educational curriculum developed in response to the pandemic and aimed toward OMS resident education

CK2 inhibitor CX-4945 destabilizes NOTCH1 and synergizes with JQ1 against human T-acute lymphoblastic leukemic cells

Here we show that CK2 inhibition by CX-4945 destabilizes NOTCH1 and synergizes with JQ1 to induce apoptosis in human T-ALL cells, implicating an alternative strategy to target NOTCH1 signaling in refractory/relapsed T-ALL

Novel prognostic nomogram for predicting recurrence-free survival in medullary thyroid carcinoma

AimsRecently, there have been attempts to improve prognostication and therefore better guide treatment for patients with medullary thyroid carcinoma (MTC). In 2022, the International MTC Grading System (IMTCGS) was developed and validated using a multi-institutional cohort of 327 patients. The aim of the current study was to build upon the findings of the IMTCGS to develop and validate a prognostic nomogram to predict recurrence-free survival (RFS) in MTC.Methods and ResultsData from 300 patients with MTC from five centres across the USA, Europe, and Australia were used to develop a prognostic nomogram that included the following variables: age, sex, AJCC stage, tumour size, mitotic count, necrosis, Ki67 index, lymphovascular invasion, microscopic extrathyroidal extension, and margin status. A process of 10-fold cross-validation was used to optimize the model's performance. To assess discrimination and calibration, the area-under-the-curve (AUC) of a receiver operating characteristic (ROC) curve, concordance-index (C-index), and dissimilarity index (D-index) were calculated. Finally, the model was externally validated using a separate cohort of 87 MTC patients. The model demonstrated very strong performance, with an AUC of 0.94, a C-index of 0.876, and a D-index of 19.06. When applied to the external validation cohort, the model had an AUC of 0.9.ConclusionsUsing well-established clinicopathological prognostic variables, we developed and externally validated a robust multivariate prediction model for RFS in patients with resected MTC. The model demonstrates excellent predictive capability and may help guide decisions on patient management. The nomogram is freely available online at .Building upon the International Medullary Thyroid Carcinoma (MTC) Grading System (IMTCGS) developed in 2022, this study presents a prognostic nomogram to predict recurrence-free survival in MTC. The model was created using data from 300 MTC patients and was externally validated in a separate cohort. The nomogram is available at . imag

Association of the Genomic Profile of Medullary Thyroid Carcinoma with Tumor Characteristics and Clinical Outcomes in an International Multicenter Study

Purpose: The prognostic importance of RET and RAS mutations and their relationship to clinicopathologic parameters and outcomes in medullary thyroid carcinoma (MTC) need to be clarified. Experimental Design: A multicenter retrospective cohort study was performed utilizing data from 290 patients with MTC. The molecular profile was determined and associations were examined with clinicopathologic data and outcomes. Results: RET germ line mutations were detected in 40 patients (16.3%). Somatic RET and RAS mutations occurred in 135 (46.9%) and 57 (19.8%) patients, respectively. RETM918T was the most common somatic RET mutation (n = 75). RET somatic mutations were associated with male sex, larger tumor size, advanced American Joint Committee Cancer (AJCC) stage, vascular invasion, and high International Medullary Thyroid Carcinoma Grading System (IMTCGS) grade. When compared with other RET somatic mutations, RETM918T was associated with younger age, AJCC (eighth edition) IV, vascular invasion, extrathyroidal extension, and positive margins. RET somatic or germ line mutations were significantly associated with reduced distant metastasis-free survival on univariate analysis, but there were no significant independent associations on multivariable analysis, after adjusting for tumor grade and stage. There were no significant differences in outcomes between RET somatic and RET germ line mutations, or between RETM918T and other RET mutations. Other recurrent molecular alterations included TP53 (4.2%), ARID2 (2.9%), SETD2 (2.9%), KMT2A (2.9%), and KMT2C (2.9%). Among them, TP53 mutations were associated with decreased overall survival (OS) and disease-specific survival (DSS), independently of tumor grade and AJCC stage. Conclusions: RET somatic mutations were associated with high-grade, aggressive primary tumor characteristics, and decreased distant metastatic-free survival but this relationship was not significant after accounting for tumor grade and disease stage. RETM918T was associated with aggressive primary tumors but was not independently associated with clinical outcomes. TP53 mutation may represent an adverse molecular event associated with decreased OS and DSS in MTC, but its prognostic value needs to be confirmed in future studies