Intratumoral Cell Neighborhoods Coordinate Outcomes in Pancreatic Ductal Adenocarcinoma
Recommended Citation
Wattenberg MM, Colby S, Garrido-Laguna I, Xue Y, Chang R, Delman D, Lee J, Affolter K, Mulvihill SJ, Beg MS, Wang-Gillam A, Wade JL, 3rd, Guthrie KA, Chiorean EG, Ahmad SA, Lowy AM, Philip PA, Sohal DPS, and Beatty GL. Intra-tumoral cell neighborhoods coordinate outcomes in pancreatic ductal adenocarcinoma. Gastroenterology 2024.
Document Type
Article
Publication Date
1-18-2024
Publication Title
Gastroenterology
Abstract
BACKGROUND AND AIMS: Pancreatic ductal adenocarcinoma (PDA) is a highly lethal disease characterized by a spatially heterogeneous tumor microenvironment. Within the PDA microenvironment, cells organize into communities where cell fate is influenced by neighboring cells of diverse ontogeny and function. However, it remains unclear how cell neighborhoods in the tumor microenvironment evolve with treatment and impact clinical outcomes.
METHODS: Here, using automated chromogenic multiplex immunohistochemistry and unsupervised computational image analysis of human PDA tumors, we investigated cell neighborhoods in surgically resected tumors from patients with chemotherapy-naïve PDA (n = 59) and neoadjuvant chemotherapy-treated PDA (n = 57). Single cells were defined by lineage markers (CD3, CD8, Foxp3, CD68, CK19), proliferation (Ki67), and neighboring cells.
RESULTS: Distinct intratumoral immune and tumor cell subsets were defined by neighboring cells. Higher content of stromal-associated macrophages was seen in chemotherapy-naïve tumors from long-term survivors (overall survival >3 years) compared with short-term survivors (overall survival <1 >year), whereas immune-excluded tumor cells were higher in short-term survivors. Chemotherapy-treated vs -naïve tumors showed lower content of tumor-associated T cells and macrophages but similar densities of stromal-associated immune cells. However, proliferating tumor cell subsets with immune-rich neighborhoods were higher in chemotherapy-treated tumors. In a blinded analysis of tumors from patients treated with neoadjuvant chemotherapy, a composite index comprising lower quantities of immune-excluded tumor cells and higher spatially distinct immune cell subsets was associated with prolonged survival.
CONCLUSIONS: Together, these data provide new insights into discrete cell communities in PDA and show their clinical relevance.
PubMed ID
38244727
ePublication
ePub ahead of print
