“Engineered Nanowires for miRNA-Mediated Control of T Cell Exhaustion” - Shaylyn Grier, Ph.D. student, Ankur Singh, Advisor.
Persistent antigen exposure in cancer and chronic infection can drive T cell exhaustion, limiting the long-term effectiveness of adoptive cell therapies. A stem-like subset of exhausted T cells, known as progenitor exhausted T cells (Texprog), is associated with more durable immune responses and improved responses to immunotherapy, but is often present at low and variable levels. Here, we developed a silicon nanowire-based platform to deliver regulatory microRNAs directly into naïve mouse and human T cells, enabling early cellular programming before differentiation. Across mouse and human tumor models, including a three-dimensional diffuse large B-cell lymphoma organoid system, microRNA delivery increased features associated with Texprog, reduced signs of terminal exhaustion, improved cell survival, and maintained T cell function. These findings suggest that nanowire-mediated microRNA delivery can guide T cells toward a more persistent and therapeutically beneficial state, providing a promising strategy to enhance the effectiveness of adoptive T cell therapies.
"Transcriptional Drivers of Impaired B Cell Immunity in Lymphoma Survivors" - Rachel Ringquist, Ph.D., Ankur Singh, Advisor.
R-CHOP, a combination of chemotherapy and the anti-CD20 antibody rituximab, is the standard first-line treatment for diffuse large B-cell lymphoma (DLBCL). While highly effective, recent studies have shown that patients treated with R-CHOP exhibit significantly diminished B cell responses even years after treatment concludes. Here, we aimed to identify transcriptional drivers of these diminished responses using an in vitro immune organoid platform that recapitulates B cell activation and maturation within the lymph node microenvironment. We profiled B cells from lymphoma survivors and found that our organoid system stratified donors into low, moderate, and high responders following influenza stimulation. Using single-cell RNA sequencing we identified unique transcriptional programs driving the observed functional differences between low and high responders. Furthermore, through single-cell BCR sequencing, we identified key differences in the clonal B cell responses between high and low responders. These results demonstrate that immune organoids can capture clinically meaningful heterogeneity in post-treatment B cell function, offering a platform for dissecting the mechanisms underlying impaired humoral immunity in lymphoma survivors.
The Immunoengineering Training Seminar Series is supported by the NIH T32 Research Training Program in Immunoengineering and housed within the Center for Immunoengineering at Georgia Tech.
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