TY - JOUR
T1 - Intratumoral Cell Neighborhoods Coordinate Outcomes in Pancreatic Ductal Adenocarcinoma
AU - Wattenberg, Max M.
AU - Colby, Sarah
AU - Garrido-Laguna, Ignacio
AU - Xue, Yuqing
AU - Chang, Renee
AU - Delman, Devora
AU - Lee, Jesse
AU - Affolter, Kajsa
AU - Mulvihill, Sean J.
AU - Beg, M. Shaalan
AU - Wang-Gillam, Andrea
AU - Wade, James Lloyd
AU - Guthrie, Katherine A.
AU - Chiorean, E. Gabriela
AU - Ahmad, Syed A.
AU - Lowy, Andrew M.
AU - Philip, Philip Agop
AU - Sohal, Davendra P.S.
AU - Beatty, Gregory L.
N1 - Publisher Copyright:
© 2024 AGA Institute
PY - 2024/6
Y1 - 2024/6
N2 - Background & 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.
AB - Background & 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.
KW - Biomarkers
KW - Immune Cells
KW - Inflammation
KW - Pancreatic Cancer
KW - Tumor Microenvironment
UR - http://www.scopus.com/inward/record.url?scp=85190823910&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2024.01.013
DO - 10.1053/j.gastro.2024.01.013
M3 - Article
C2 - 38244727
AN - SCOPUS:85190823910
SN - 0016-5085
VL - 166
SP - 1114
EP - 1129
JO - Gastroenterology
JF - Gastroenterology
IS - 6
ER -