Development of human pancreatic cancer avatars as a model for dynamic immune landscape profiling and personalised therapy

Pancreatic ductal adenocarcinoma (PDAC) is the most common form of
pancreatic cancer, a disease with dismal overall survival.
Advances in treatment are hindered by a lack of preclinical models. Here
we show how a personalised organotypic ‘avatar’ created from
resected tissue, allows spatial and temporal reporting on a
complete in situ tumour microenvironment, and mirrors clinical responses.
Our perfusion culture method extends tumour slice viability,
maintaining stable tumour content, metabolism,
stromal composition, and immune cell populations for 12 days.
Using multiplexed immunofluorescence and spatial transcriptomics, we
identify immune neighbourhoods and potential for immunotherapy. We
employed avatars to assess the impact of a pre-clinically
validated metabolic therapy and show recovery of stromal and
immune phenotypes and tumour re-differentiation. To determine clinical
relevance, we monitored avatar response to gemcitabine treatment
and identified a patient avatar-predicable response from clinical
follow-up. Thus, avatars provide valuable information for the syngeneic
testing of novel therapeutics and a truly personalised therapeutic
assessment platform for patients.