Chengxin Yu

Distinctively, pancreatic ductal adenocarcinoma (PDAC) consists of sparse tumour lesions intertwined with extensive desmoplastic stroma. The complexity of tumour-microenvironment interactions within this desmoplasia poses a challenge for accurate tumour profiling and patient stratification, and characterizes a profoundly chemoresistant tumour. Here we mapped the spatial relationships between tumour, stroma, and immune cell compartments delineating tumour and microenvironment types that expand the classical to basal spectrum of human PDAC. We used imaging mass cytometry to profile the in situ multi-cellular organization of 81 cell types in resected cases with paired whole genome sequencing. Cell types, functions, and pathway activation were distributed as highly reproducible environments in discrete locations throughout these tumours, which we deep-profiled using laser-capture mass spectrometry. We show that the connections between tumour phenotypes, vascularization, immune response, and stromal biophysical state are reinforced by genomic aberrations, altered by treatment, and associated with patient outcome. Predictive machine-learning models showed that spatial single cell data outperformed genomic or clinical features but integrated multi-omics models provide the best prediction of patient survival with compressed models requiring only 10 non-redundant robust molecular measures associated with the phenotypic spectrum of PDAC. Together, these findings define a phenotypic and molecular framework of PDAC that captures tumour-microenvironment co-dependencies and offers a refined basis for patient stratification and therapeutic targeting.

Antigen specificity and functionality of predominant TCRs from tumors from immunotherapy treated mice.

Single cell transcriptional atlas following anti-PDL1 or agonistic anti-CD40

CD4 T cells and tumor antigen are required for anti-CD40 driven TSTEM accumulation in PDA

Comparison of human and murine tumor-infiltrating CD8 T cells.

IL15C synergizes with immunotherapy to target poorly immunogenic KPC2 tumors

CD8 T cell differentiation in PDA.

IL-15C promotes the activity of dual therapy by promoting T-bet in tumor-infiltrating T cells

A fraction of TSTEM and TEFF are in the vasculature in dLN and tumor