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Immunotherapies targeting the immune checkpoint receptor programmed cell death protein 1 (PD-1) have shown remarkable efficacy in treating cancer. CD4+CD25hiFoxP3+ Tregs are critical regulators of immune responses in autoimmunity and malignancies, but the functional status of human Tregs expressing PD-1 remains unclear. We examined functional and molecular features of PD-1hi Tregs in healthy subjects and patients with glioblastoma multiforme (GBM), combining functional assays, RNA sequencing, and cytometry by time of flight (CyTOF). In both patients with GBM and healthy subjects, circulating PD-1hi Tregs displayed reduced suppression of CD4+ effector T cells, production of IFN-γ, and molecular signatures of exhaustion. Transcriptional profiling of tumor-resident Tregs revealed that several genes coexpressed with PD-1 and associated with IFN-γ production and exhaustion as well as enrichment in exhaustion signatures compared with circulating PD-1hi Tregs. CyTOF analysis of circulating and tumor-infiltrating Tregs from patients with GBM treated with PD-1-blocking antibodies revealed that treatment shifts the profile of circulating Tregs toward a more exhausted phenotype reminiscent of that of tumor-infiltrating Tregs, further increasing IFN-γ production. Thus, high PD-1 expression on human Tregs identifies dysfunctional, exhausted Tregs secreting IFN-γ that exist in healthy individuals and are enriched in tumor infiltrates, possibly losing function as they attempt to modulate the antitumoral immune responses.

BACKGROUND: Despite substantial research on medical student mistreatment, there is scant quantitative data on microaggressions in US medical education. OBJECTIVE: To assess US medical students' experiences of microaggressions and how these experiences influenced students' mental health and medical school satisfaction. DESIGN AND PARTICIPANTS: We conducted a crosssectional, online survey of US medical students' experiences of microaggressions. MAIN MEASURES: The primary outcome was a positive depression screen on the 2-item Patient Health Questionnaire (PHQ-2). Medical school satisfaction was a secondary outcome. We used logistic regression to model the association between respondents' reported microaggression frequency and the likelihood of a positive PHQ-2 screen. For secondary outcomes, we used the chi-squared statistic to test associations between microaggression exposure and medical school satisfaction. KEY RESULTS: Out of 759 respondents, 61% experienced at least one microaggression weekly. Gender (64.4%), race/ethnicity (60.5%), and age (40.9%) were the most commonly cited reasons for experiencing microaggressions. Increased microaggression frequency was associated with a positive depression screen in a dose-response relationship, with second, third, and fourth (highest) quartiles of microaggression frequency having odds ratios of 2.71 (95% CI: 1-7.9), 3.87 (95% CI: 1. , relative to the first quartile. Medical students who experienced at least one microaggression weekly were more likely to consider medical school transfer (14.5% vs 4.7%, p<0.001) and withdrawal (18.2% vs 5.7%, p<0.001) and more likely to believe microaggressions were a normal part of medical school culture (62.3% vs 32.1%) compared to students who experienced microaggressions less frequently. CONCLUSIONS: To our knowledge, this is the largest study on the experiences and influences of microaggressions among a national sample of US medical students. Our major findings were that microaggressions are frequent occurrences and that the experience of microaggressions was associated with a positive depression screening and decreased medical school satisfaction.

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