Biology subjects

Weist, B. M.

Publications and source records attributed to Weist, B. M..

3 recordsLinked to original sources

bioRxiv2026

MHCII+ cancer-associated fibroblasts promote antitumor immunity in pancreatic cancer

The functions of major histocompatibility complex class II molecule-expressing cancer-associated fibroblasts (MHCII+CAFs) in pancreatic cancer remain controversial. MHCII+CAFs are primarily described as immunosuppressive, as MHCII allows for direct interaction with, and support of, regulatory T cells (Tregs). However, MHCII+CAF functions may be more complex depending on their origins and their cellular interactions within the tumor microenvironment. Here, using orthotopic models of pancreatic cancer, we show that conventional CD4+ T cells and their production of Interferon gamma (IFN{gamma}) increased MHCII+CAFs in tumors. Acute depletion of Tregs using Foxp3DTR mice revealed that Tregs suppress the abundance of MHCII+CAFs in tumors by inhibiting CD4 T cell responses that can directly control primary tumor growth and metastatic progression. Functionally, MHCII expression on fibroblasts was required for CD4 T cell control of PDAC progression upon Treg ablation. Collectively, our findings identify an IFN{gamma}-driven, antitumor activity of MHCII expression on CAFs and reveal that CAFs may be harnessed to promote adaptive immunity to PDAC.

immunology↗

bioRxiv2025

Intratumoral Treg ablation is sufficient to mediate tumor control systemically without autoimmunity

Regulatory T cells (Tregs) infiltrate most tumors, yet whether they suppress immune responses directly within tumor tissues is not clear. We used intratumoral (IT) delivery of diphtheria toxin (DT) in Foxp3DTR mice to deplete IT Tregs while leaving peripheral Tregs intact. IT delivery of DT reduced Treg frequencies in the tumor, which promoted potent tumor control without autoimmunity. Interestingly, this control was principally mediated by CD4+ T cells, whereas CD8+ T cells only contributed when CD4+ T cells were absent. While conventional dendritic cells (cDCs) were required to clear tumors, Batf3+ cDC1s were dispensable. Distant secondary tumors, mimicking metastases, were also controlled by IT Treg ablation. Mechanistically, IT Tregs suppressed antitumor T cell responses by blocking the acquisition of tumor antigen by cDC2s. Importantly, similar mechanisms of control were observed using a clinically translatable IT Treg-depleting anti-CCR8 antibody and reveal a distinct therapeutic strategy that leverages cDC2s and CD4+ T cells.

cancer biology↗

bioRxiv2019

Factors that influence the thymic selection of CD8αα intraepithelial lymphocytes

Thymocytes bearing {beta} T cell receptors (TCR{beta}) with high affinity for self-peptide-MHC complexes undergo negative selection or are diverted to alternate T cell lineages, a process termed agonist selection. Among thymocytes bearing TCRs restricted to MHC class I, agonist selection can lead to the development of precursors that can home to the gut and give rise to CD8-expressing intraepithelial lymphocytes (CD8 IELs). The factors that influence the choice between negative selection versus CD8 IEL development remain largely unknown. Using a synchronized thymic tissue slice model that supports both negative selection and CD8IEL development, we show that the affinity threshold for CD8 IEL development is higher than for negative selection. We also investigate the impact of peptide presenting cells and cytokines, and the migration patterns associated with these alternative cell fates. Our data highlight the roles of TCR affinity and the thymic microenvironments on T cell fate.

immunology↗