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Targeting immune receptors on T cells is a common strategy to treat cancer and autoimmunity. Frequently, this is accomplished through monoclonal antibodies targeting the ligand binding sites of stimulatory or inhibitory co-receptors. Blocking ligand binding prevents downstream signalling and modulates specific T cell functions. Since 1985, the FDA has approved over 100 monoclonal antibodies against immune receptors. This therapeutic approach significantly improved the care of patients with numerous immune-related conditions; however, many patients are unresponsive, and some develop immune-related adverse events. One reason for that is the lack of consideration for the localization of these receptors on the cell surface of the immune cells in the context of the immune synapse. In addition to blocking ligand binding, changing the location of these receptors on the cell surface within the different compartments of the immunological synapse could serve as an alternative, efficient, and safer approach to treating these patients. This review discusses the potential therapeutic advantages of altering proteins' localization within the immune synapse and summarizes published work in this field. It also discusses the novel use of bispecific antibodies to induce the clustering of receptors on the cell surface. It presents the rationale for developing novel antibodies, targeting the organization of signalling receptor complexes on the cell surface. This approach offers an innovative and emerging technology to treat cancer patients resistant to current immunotherapies., (© 2024 John Wiley & Sons Ltd.)

There are limited studies regarding the attainment of the Accreditation Council for Genetic Counseling Practice-Based Competencies by genetic counseling students who complete clinical rotations in an in-person setting versus in a remote setting that incudes telephone and/or video patient encounters. This study explored the perceptions of 17 patient-facing genetic counselors who had served as supervisors for genetic counseling students regarding student attainment of practice-based competencies in in-person compared to remote rotations. Participants were recruited through an American Board of Genetic Counseling eblast and were required to have at least 2 years of clinical experience and experience providing genetic counseling supervision for at least one in-person rotation and one remote rotation. Four focus groups were created comprising genetic counselors from various practice disciplines. Discussion focused on potential differences and similarities in supervisor perceptions of student attainment of each clinical practice-based competency, and whether there were any concerns about students being able to attain each competency in remote rotations. Overall, participants discussed that genetic counseling students' attainment of clinical competencies through remote rotations was comparable to in-person rotations; however, 15 themes were identified illustrating differences reported by participants in how they observed these skills being performed by students in in-person versus remote clinical settings. The findings of this study highlight important considerations when developing a remote rotation, as well as ways in which certain clinical skills may be further enhanced through a combination of both in-person and remote clinical experiences. A noted limitation of remote rotations is that students have less of an opportunity to interact with other providers, and so may require other opportunities for interprofessionalism and to understand their role as part of a larger organization. Further study is required to elucidate differences between telephone and video clinics, as well as potential differences pertaining to various specialty areas of practice., (© 2024 The Authors. Journal of Genetic Counseling published by Wiley Periodicals LLC on behalf of National Society of Genetic Counselors.)

Improving the management of metastasis in pancreatic neuroendocrine tumors (PanNETs) is critical, as nearly half of patients with PanNETs present with liver metastases, and this accounts for the majority of patient mortality. We identified angiopoietin-2 (ANGPT2) as one of the most upregulated angiogenic factors in RNA-Seq data from human PanNET liver metastases and found that higher ANGPT2 expression correlated with poor survival rates. Immunohistochemical staining revealed that ANGPT2 was localized to the endothelial cells of blood vessels in PanNET liver metastases. We observed an association between the upregulation of endothelial ANGPT2 and liver metastatic progression in both patients and transgenic mouse models of PanNETs. In human and mouse PanNET liver metastases, ANGPT2 upregulation coincided with poor T cell infiltration, indicative of an immunosuppressive tumor microenvironment. Notably, both pharmacologic inhibition and genetic deletion of ANGPT2 in PanNET mouse models slowed the growth of PanNET liver metastases. Furthermore, pharmacologic inhibition of ANGPT2 promoted T cell infiltration and activation in liver metastases, improving the survival of mice with metastatic PanNETs. These changes were accompanied by reduced plasma leakage and improved vascular integrity in metastases. Together, these findings suggest that ANGPT2 blockade may be an effective strategy for promoting T cell infiltration and immunostimulatory reprogramming to reduce the growth of liver metastases in PanNETs.

Cancer immunotherapy relies on improving T cell effector functions against malignancies, but despite the identification of several key transcription factors (TFs), the biological functions of these TFs are not entirely understood. We developed and utilized a novel, clinically relevant murine model to dissect the functional properties of crucial T cell transcription factors during anti-tumor responses. Our data showed that the loss of TCF-1 in CD8 T cells also leads to loss of key stimulatory molecules such as CD28. Our data showed that TCF-1 suppresses surface NKG2D expression on naïve and activated CD8 T cells via key transcriptional factors Eomes and T-bet. Using both in vitro and in vivo models, we uncovered how TCF-1 regulates critical molecules responsible for peripheral CD8 T cell effector functions. Finally, our unique genetic and molecular approaches suggested that TCF-1 also differentially regulates essential kinases. These kinases, including LCK, LAT, ITK, PLC-γ1, P65, ERKI/II, and JAK/STATs, are required for peripheral CD8 T cell persistent function during alloimmunity. Overall, our molecular and bioinformatics data demonstrate the mechanism by which TCF-1 modulated several critical aspects of T cell function during CD8 T cell response to cancer. Summary Figure: TCF-1 is required for persistent function of CD8 T cells but dispensable for anti-tumor response. Here, we have utilized a novel mouse model that lacks TCF-1 specifically on CD8 T cells for an allogeneic transplant model. We uncovered a molecular mechanism of how TCF-1 regulates key signaling pathways at both transcriptomic and protein levels. These key molecules included LCK, LAT, ITK, PLC-γ1, p65, ERK I/II, and JAK/STAT signaling. Next, we showed that the lack of TCF-1 impacted phenotype, proinflammatory cytokine production, chemokine expression, and T cell activation. We provided clinical evidence for how these changes impact GVHD target organs (skin, small intestine, and liver). Finally, we provided evidence that TCF-1 regulates NKG2D expression on mouse naïve and activated CD8 T cells. We have shown that CD8 T cells from TCF-1 cKO mice mediate cytolytic functions via NKG2D., (© 2022. The Author(s).)

Background: The evidence review processes for adding new conditions to state newborn screening (NBS) panels rely on data from pilot studies aimed at assessing the potential benefits and harms of screening. However, the consideration of ethical, legal, and social implications (ELSI) of screening within this research has been limited. This paper outlines important ELSI issues related to newborn screening policy and practices as a resource to help researchers integrate ELSI into NBS pilot studies., Approach: Members of the Bioethics and Legal Workgroup for the Newborn Screening Translational Research Network facilitated a series of professional and public discussions aimed at engaging NBS stakeholders to identify important existing and emerging ELSI challenges accompanying NBS., Results: Through these engagement activities, we identified a set of key ELSI questions related to (1) the types of results parents may receive through newborn screening and (2) the initiation and implementation of NBS for a condition within the NBS system., Conclusion: Integrating ELSI questions into pilot studies will help NBS programs to better understand the potential impact of screening for a new condition on newborns and families, and make crucial policy decisions aimed at maximized benefits and mitigating the potential negative medical or social implications of screening.

Purpose: The Inborn Errors of Metabolism Information System (IBEM-IS) collects data on the clinical history of inborn errors of metabolism (IBEMs). The IBEM-IS is accessible to metabolic clinics nationwide and seeks to (i) influence clinical management of affected individuals and (ii) provide information to support public health decision making., Methods: Thirty centers in 21 states are enrolling persons with newborn-screened conditions, collecting information on diagnosis and treatment at the time of enrollment and all subsequent visits. Prospective data are collected using electronic capture forms allowing aggregation of information regarding outcomes for individuals affected with IBEMs., Results: A total of 1,893 subjects have been enrolled in the IBEM-IS, and more than 540,000 individual data points have been collected. Data collection has been initiated for subjects with 41 of 46 conditions on the recommended uniform screening panel; 4 conditions have more than 100 subjects enrolled. Median follow-up time for subjects with more than one visit (n = 898) is 1.5 years (interquartile range = 2.2 years). Subjects with critical conditions are more likely to have emergency letters and sick-day plans. Mortality was exclusive to children with critical conditions., Conclusion: Large-scale prospective data can be collected for individuals with rare conditions, permitting enhanced decision making for clinical management and supporting decision making in public health newborn screening programs.Genet Med 18 12, 1276-1281.