Kunisada, Y. | bioRxiv Science

bioRxiv2023

A pancreatic cancer mouse model with human immunity

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a tumor immune microenvironment (TIME) that promotes resistance to immunotherapy. A preclinical model system that facilitates studies of the TIME and its impact on the responsiveness of human PDAC to immunotherapies remains an unmet need. We report a novel mouse model, which develops metastatic human PDAC that becomes infiltrated by human immune cells recapitulating the TIME of human PDAC. The model may serve as a versatile platform to study the nature of human PDAC TIME and its response to various treatments.

cancer biology↗

bioRxiv2023

Tumor-resident regulatory T cells in pancreatic cancer express the αvβ5 integrin as a targetable activation marker

Pancreatic ductal adenocarcinoma (PDAC) has abundant immunosuppressive regulatory T cells (Tregs), which contribute to a microenvironment resistant to immunotherapy. Here, we report that Tregs in the PDAC tissue, but not those in the spleen, express the v{beta}5 integrin in addition to neuropilin-1 (NRP-1), which makes them susceptible to the iRGD tumor-penetrating peptide, which targets cells positive for v integrin- and NRP-1. As a result, long-term treatment of PDAC mice with iRGD leads to tumor-specific depletion of Tregs and improved efficacy of immune checkpoint blockade. v{beta}5 integrin+ Tregs are induced from both naive CD4+ T cells and natural Tregs upon T cell receptor stimulation, and represent a highly immunosuppressive subpopulation of CCR8+ Tregs. This study identifies the v{beta}5 integrin as a marker for activated tumor-resident Tregs, which can be targeted to achieve tumor-specific Treg depletion and thereby augment anti-tumor immunity for PDAC therapy.

cancer biology↗