PSGL-1 Blockade Induces Classical Activation of Human Tumor-associated Macrophages.

The immune suppressive microenvironment is a major culprit for difficult-to-treat solid cancers. Particularly, inhibitory tumor-associated macrophages (TAM) define the resistant nature of the tumor milieu. To define tumor-enabling mechanisms of TAMs, we analyzed molecular clinical datasets correlating cell surface receptors with the TAM infiltrate. Though P-selectin glycoprotein ligand-1 (PSGL-1) is found on other immune cells and functions as an adhesion molecule, PSGL-1 is highly expressed on TAMs across multiple tumor types. siRNA-mediated knockdown and antibody-mediated inhibition revealed a role for PSGL-1 in maintaining an immune suppressed macrophage state. PSGL-1 knockdown or inhibition enhanced proinflammatory mediator release across assays and donors in vitro. In several syngeneic mouse models, PSGL-1 blockade alone and in combination with PD-1 blockade reduced tumor growth. Using a humanized tumor model, we observed the proinflammatory TAM switch following treatment with an anti-PSGL-1 antibody. In ex vivo patient-derived tumor cultures, a PSGL-1 blocking antibody increased expression of macrophage-derived proinflammatory cytokines, as well as IFNγ, indicative of T-cell activation. Our data demonstrate that PSGL-1 blockade reprograms TAMs, offering a new therapeutic avenue to patients not responding to T-cell immunotherapies, as well as patients with tumors devoid of T cells. SIGNIFICANCE: This work is a significant and actionable advance, as it offers a novel approach to treating patients with cancer who do not respond to T-cell checkpoint inhibitors, as well as to patients with tumors lacking T-cell infiltration. We expect that this mechanism will be applicable in multiple indications characterized by infiltration of TAMs.

Gender, depressive symptoms and patterns of alcohol use among college students.

BACKGROUND: Serious alcohol-related negative consequences are associated with a number of drinking behaviors among college students. Thus, it is critical to identify students who are at greater risk for hazardous drinking. Although some studies have shown that depressive symptoms may be associated with alcohol use in this population, findings are not consistent. The current study extends previous research by investigating the relationship between depressive symptoms, daily alcohol use and compulsive drinking among college students and whether gender moderates these relationships. SAMPLING AND METHODS: The participants were 904 college students (495 females; mean age = 20.07 ± 1.85 years) who filled out questionnaires that focused on drinking behaviors and severity of depressive symptoms. RESULTS: Gender moderated the relationship between depressive symptoms and daily alcohol consumption. In male college students, worse depressive symptoms were associated with increased daily alcohol use and with greater risk for compulsive drinking. In female college students, worse depressive symptoms increased the risk for compulsive drinking, but not for greater daily alcohol use. CONCLUSIONS: Results suggest that prevention programs aimed at decreasing harmful alcohol use among college students must take into consideration the role of both gender and depressive symptoms in the development of problematic drinking behaviors.

Person-Centered Assessment and Care Planning.

The quality of dementia care rendered to individuals and families is contingent upon the quality of assessment and care planning, and the degree to which those processes are person-centered. This paper provides recommendations for assessment and care planning derived from a review of the research literature. These guidelines build upon previous recommendations published by the Alzheimer's Association, and apply to all settings, types, and stages of dementia. The target audience for these guidelines includes professionals, paraprofessionals, and direct care workers, depending on their scope of practice and training.