Lung tumor-infiltrating Treg have divergent transcriptional profiles and function linked to checkpoint blockade response.

Regulatory T cells (Treg) are conventionally viewed as suppressors of endogenous and therapy-induced antitumor immunity; however, their role in modulating responses to immune checkpoint blockade (ICB) is unclear. In this study, we integrated single-cell RNA-seq/T cell receptor sequencing (TCRseq) of >73,000 tumor-infiltrating Treg (TIL-Treg) from anti-PD-1-treated and treatment-naive non-small cell lung cancers (NSCLC) with single-cell analysis of tumor-associated antigen (TAA)-specific Treg derived from a murine tumor model. We identified 10 subsets of human TIL-Treg, most of which have high concordance with murine TIL-Treg subsets. Only one subset selectively expresses high levels of TNFRSF4 (OX40) and TNFRSF18 (GITR), whose engangement by cognate ligand mediated proliferative programs and NF-κB activation, as well as multiple genes involved in Treg suppression, including LAG3. Functionally, the OX40hiGITRhi subset is the most highly suppressive ex vivo, and its higher representation among total TIL-Treg correlated with resistance to PD-1 blockade. Unexpectedly, in the murine tumor model, we found that virtually all TIL-Treg-expressing T cell receptors that are specific for TAA fully develop a distinct TH1-like signature over a 2-week period after entry into the tumor, down-regulating FoxP3 and up-regulating expression of TBX21 (Tbet), IFNG, and certain proinflammatory granzymes. Transfer learning of a gene score from the murine TAA-specific TH1-like Treg subset to the human single-cell dataset revealed a highly analogous subcluster that was enriched in anti-PD-1-responding tumors. These findings demonstrate that TIL-Treg partition into multiple distinct transcriptionally defined subsets with potentially opposing effects on ICB-induced antitumor immunity and suggest that TAA-specific TIL-Treg may positively contribute to antitumor responses.

Integrating Cultural Relevance into a Behavioral mHealth Intervention for Native American Youth.

Native American communities are disproportionately affected by a number of behavioral health disparities, including higher rates of depression, substance abuse, and suicide. As mobile health (mHealth) interventions gain traction as methods for addressing these disparities, they continue to lack relevance to Native American youth. In an effort to explore the design of relevant behavioral mHealth intervention for Native American communities, we have developed ARORA (Amplifying Resilience Over Restricted Internet Access), a prototype behavioral mHealth intervention that has been co-designed with Native American youth, a community advisory board, and a clinical psychologist. In this paper, we qualitatively analyze our co-design and focus group sessions using a grounded theory approach and identify the key themes that Native American community members have identified as being critical components of relevant mHealth designs. Notably, we find that the Native American youth who participated in our focus groups desired a greater level of didactic interaction with cultural and behavioral health elements. We conclude with a discussion of the significant challenges we faced in our efforts to co-design software with Native American stakeholders and provide recommendations that might guide other HCI researchers and designers through challenges that arise during the process of cross-cultural design.

Advancing global citizens: afterschool and out-of-school time as common ground for civil society.

The key importance of after-school and out-of-school time in a democratic society is the experience of activities and programs providing a common ground that extends the play of childhood into leadership opportunities for youthful learning and exploration of the world. The authors hypothesize that by focusing civic attention on the developmental quality of these out-of-school settings and time frames, objectives will also be better understood and reliable.