CLDN18.2 BiTE Engages Effector and Regulatory T Cells for Antitumor Immune Response in Preclinical Models of Pancreatic Cancer.

BACKGROUND & AIMS: BiTE (bispecific T-cell engager) immune therapy has demonstrated clinical activity in multiple tumor indications, but its influence in the tumor microenvironment remains unclear. CLDN18.2 is overexpressed in solid tumors including gastric cancer (GC) and pancreatic ductal adenocarcinoma (PDAC), both of which are characterized by the presence of immunosuppressive cells, including regulatory T cells (Tregs) and few effector T cells (Teffs). METHODS: We evaluated the activity of AMG 910, a CLDN18.2-targeted half-life extended (HLE) BiTE molecule, in GC and PDAC preclinical models and cocultured Tregs and Teffs in the presence of CLDN18.2-HLE-BiTE. RESULTS: AMG 910 induced potent, specific cytotoxicity in GC and PDAC cell lines. In GSU and SNU-620 GC xenograft models, AMG 910 engaged human CD3+ T cells with tumor cells, resulting in significant antitumor activity. AMG 910 monotherapy, in combination with a programmed death-1 (PD-1) inhibitor, suppressed tumor growth and enhanced survival in an orthotopic Panc4.14 PDAC model. Moreover, Treg infusion enhanced the antitumor efficacy of AMG 910 in the Panc4.14 model. In syngeneic KPC models of PDAC, treatment with a mouse surrogate CLDN18.2-HLE-BiTE (muCLDN18.2-HLE-BiTE) or the combination with an anti-PD-1 antibody significantly inhibited tumor growth. Tregs isolated from mice bearing KPC tumors that were treated with muCLDN18.2-HLE-BiTE showed decreased T cell suppressive activity and enhanced Teff cytotoxic activity, associated with increased production of type I cytokines and expression of Teff gene signatures. CONCLUSIONS: Our data suggest that BiTE molecule treatment converts Treg function from immunosuppressive to immune enhancing, leading to antitumor activity in immunologically "cold" tumors.

Community Engagement in Implementation Science: the Impact of Community Engagement Activities in the DECIPHeR Alliance.

Background: The translation of evidence-based interventions into practice settings remains challenging. Implementation science aims to bridge the evidence-to-practice gap by understanding multilevel contexts and tailoring evidence-based interventions accordingly. Engaging community partners who possess timely, local knowledge is crucial for this process to be successful. The Disparities Elimination through Coordinated Interventions to Prevent and Control Heart and Lung Disease Risk (DECIPHeR) Alliance aims to address cardiopulmonary health disparities by engaging diverse community partners to improve the implementation of evidence-based interventions. The goal of the Community Engagement Subcommittee is to strengthen community engagement practice across DECIPHeR. This paper presents the subcommittee's "Why We Engage Communities" statement that outlines why community engagement is critical for implementation science. The paper also provides case examples of DECIPHeR community engagement activities. Methods: To develop the "Why We Engage Communities" statement, we conducted a literature review, surveyed subcommittee members to assess the importance of community engagement in their work, and integrated community partner feedback. We synthesize the findings into three key themes and present examples of community engagement activities and their impact across DECIPHeR projects. Results: The statement presents three themes that illustrate why community engagement increases the impact of implementation and health equity research. Community engagement (1) engages local knowledge and expertise, (2) promotes authentic relationships, and (3) builds community and researcher capacity. The statement provides a guiding framework for strengthening DECIPHeR research and enhancing community partnerships. Conclusion: Community engagement can improve the implementation of evidence-based interventions across diverse settings, improving intervention effectiveness in underserved communities and furthering health equity.

The C. elegans gonadal sheath Sh1 cells extend asymmetrically over a differentiating germ cell population in the proliferative zone.

The Caenorhabditis elegans adult hermaphrodite germline is surrounded by a thin tube formed by somatic sheath cells that support germ cells as they mature from the stem-like mitotic state through meiosis, gametogenesis, and ovulation. Recently, we discovered that the distal Sh1 sheath cells associate with mitotic germ cells as they exit the niche Gordon et al., 2020. Here, we report that these sheath-associated germ cells differentiate first in animals with temperature-sensitive mutations affecting germ cell state, and stem-like germ cells are maintained distal to the Sh1 boundary. We analyze several markers of the distal sheath, which is best visualized with endogenously tagged membrane proteins, as overexpressed fluorescent proteins fail to localize to distal membrane processes and can cause gonad morphology defects. However, such reagents with highly variable expression can be used to determine the relative positions of the two Sh1 cells, one of which often extends further distal than the other.