877 PSGL-1 blocking antibodies repolarize tumor associated macrophages, reduce suppressive myeloid populations and induce inflammation in the tumor microenvironment, leading to suppression of tumor growth

BackgroundSuppressive myeloid cell populations in the tumor microenvironment (TME) are associated with worse survival of cancer patients and low effectiveness of T cell checkpoint inhibitors. Recently, several early clinical trials have produced positive data for therapies aimed at repolarizing immuno-suppressive myeloid populations in the TME. One new macrophage repolarizing target, PSGL-1 (P-selectin glycoprotein ligand-1), is expressed at high levels on suppressive tumor-associated macrophages (TAMs) and in vitro differentiated M2 macrophages. PSGL-1 has been shown to have an immune-modulatory activity, which includes its role in maintaining an immuno-suppressive macrophage state.MethodsTo assess the ability of PSGL-1 antibodies to convert macrophages and the tumor microenvironment from an immuno-suppressive toward a pro-inflammatory state, we employed in vitro primary macrophage and multi-cellular assays, ex vivo patient-derived tumor cultures, and a humanized mouse PDX model.ResultsWe have determined that our lead anti-PSGL-1 antibody repolarized M2-like macrophages to a more M1-like state both phenotypically and functionally as assessed in primary in vitro macrophage assays. Transcriptomics profiling of M2c macrophages showed that the anti-PSGL-1 antibody upregulated TNF-alpha/NF-kB and chemokine-mediated signaling, while downregulating oxidative phosphorylation, fatty acid metabolism and Myc signaling pathways, consistent with a broad M2-to-M1 shift of the macrophage state. Furthermore, these repolarized M1-like macrophages enhanced the inflammatory response in complex multi-cellular assays.Pre-clinical efficacy of the anti-PSGL-1 antibody was demonstrated using ex vivo cultures of fresh patient-derived tumors that preserve the cellular heterogeneity of the TME. Anti-PSGL-1 increased production of inflammatory cytokines and chemokines involved in immune activation of the TME and T cell recruitment.Lastly, our lead anti-PSGL-1 antibody also showed in vivo anti-tumor effect in a humanized mouse PDX model of melanoma. The antibody suppressed tumor growth to a significantly greater degree compared to anti-PD-1. At the cellular and molecular levels, the anti-PSGL-1 treatment led to a more enhanced inflammatory microenvironment, including a reduced M2:M1 macrophage ratio, and an increase in systemic pro-inflammatory mediators. Compared to anti-PD-1 monotherapy, anti-PSGL-1 alone and in combination with anti-PD-1 increased the fraction of effector CD8+ T cells among the infiltrating T cells. Significant combination effects of anti-PSGL-1 plus anti-PD-1 were seen at the cellular and molecular levels within the tumor tissue, the spleen, and peripheral blood.ConclusionsThe data presented here provide biological and mechanistic support for clinical testing of antibodies targeting PSGL-1 for the treatment of cancer.Ethics ApprovalAll legal and ethical requirements were met with regards to the humane treatment of animals described in the study. The animal study was conducted in compliance with IACUC PROTO202000042 and the institutional assurance certification of the University of Massachusetts Medical School. The University of Massachusetts Medical School is fully accredited by AAALAC and has an Animal Welfare Assurance on file with the Office of Laboratory Animal Welfare (OLAW).

Adapting Open Dialogue for Early-Onset Psychosis in Latvia: Barriers and Facilitators

Open Dialogue (OD) is the Finnish crisis intervention approach based on an open dialogue involving various professionals and a trusted person of the patient. This publication has demonstrated both clinical and economic benefits from the implementation of the principles of OD. The implementation of this approach was started in Latvia in cooperation with Dr. D. Ziedonis from the Department of Psychiatry, University of Massachusetts Medical School (today working at University of California San Diego), by translating into Latvian “The Key Elements of Dialogic Practice in Open Dialogue” and carrying out expert consensus panel discussions on the barriers and facilitators of the approach. The obstacles are linked with the lack of education in family therapy, lack of resources, possible problems of cooperation among professionals, and the existing standard practice where there are no active home visits in crisis situations. At the same time, positive elements that are close to Latvian psychiatry can be observed in the OD approach, for instance, the importance of a clinical conversation and listening to the points of views of family members encourage psychiatrists in Latvia to use this approach. The setting of OD could be community-based mental health centres as well as inpatient psychiatric departments dealing with acutely psychotic patients. OD can be a valuable addition and alternative in the case of new psychotic patients when treatment with medications is not efficient, and the patient is not favourably disposed to the use of medications, but nevertheless is seeking help.

Linking Kids with Trauma to Evidence-Based Treatment: Implementation of a Centralized Referral System at the Child Trauma Training Center at the University of Massachusetts Medical School

At a time when the general standard of child welfare and mental health provision has been improving, some important groups in Massachusetts remain under-served. One such is children suffering from trauma. Despite various state-wide efforts to educate professionals about the evidence-based treatments available, trauma sufferers have typically faced long waits to receive these treatments, with average waiting times at some larger mental health agencies stretching to four or even six months. In this brief, we are presenting the implementation of a highly innovative Centralized Referral System – LINK-KID – developed at the Child Trauma Training Center (CTTC) at the University of Massachusetts Medical School. LINK-KID referral system connects children in need of evidence-based trauma treatment with mental health providers who have been trained in these treatments.

Education Research: A framework for global health curricula for neurology trainees

As the global burden of neurologic disease increases, educating future neurologists about the principles of global health through global health curricula is of utmost importance. However, few neurology residency training programs have developed and implemented comprehensive global health curricula. This report outlines the design, implementation, and evaluation of the University of Massachusetts Medical School neurology residency global health curriculum. Using accepted curriculum development methods and incorporating an innovative use of technology, we created a global health curriculum focused on neurology to engage trainees. The implementation of curricula and organization of elective opportunities also incorporates learning objectives and an evaluation process. The University of Massachusetts Medical School neurology global health curriculum can be used as a framework for other residency programs developing global health programs. Global health education increases young neurologists' awareness of the growing burden of neurologic disease and, subsequently, may motivate them to address the need for neurologic expertise around the world.

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