TY - JOUR
T1 - Quantitative Spatial Profiling of Immune Populations in Pancreatic Ductal Adenocarcinoma Reveals Tumor Microenvironment Heterogeneity and Prognostic Biomarkers
AU - Mi, Haoyang
AU - Sivagnanam, Shamilene
AU - Betts, Courtney B.
AU - Liudahl, Shannon M.
AU - Jaffee, Elizabeth M.
AU - Coussens, Lisa M.
AU - Popel, Aleksander S.
N1 - Publisher Copyright:
© 2022 The Authors; Published by the American Association for Cancer Research.
PY - 2022/12/1
Y1 - 2022/12/1
N2 - Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with poor 5-year survival rates, necessitating identification of novel therapeutic targets. Elucidating the biology of the tumor immune microenvironment (TiME) can provide vital insights into mechanisms of tumor progression. In this study, we developed a quantitative image processing platform to analyze sequential multiplexed IHC data from archival PDAC tissue resection specimens. A 27-plex marker panel was employed to simultaneously phenotype cell populations and their functional states, followed by a computational workflow to interrogate the immune contextures of the TiME in search of potential biomarkers. The PDAC TiME reflected a low-immunogenic ecosystem with both high intratumoral and intertumoral heterogeneity. Spatial analysis revealed that the relative distance between IL10+ myelomonocytes, PD-1+ CD4+ T cells, and granzyme B+ CD8+ T cells correlated significantly with survival, from which a spatial proximity signature termed imRS was derived that correlated with PDAC patient survival. Furthermore, spatial enrichment of CD8+ T cells in lymphoid aggregates was also linked to improved survival. Altogether, these findings indicate that thePDAC TiME, generally considered immuno-dormant or immunosuppressive, is a spatially nuanced ecosystem orchestrated by ordered immune hierarchies. This new understanding of spatial complexity may guide novel treatment strategies for PDAC.
AB - Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with poor 5-year survival rates, necessitating identification of novel therapeutic targets. Elucidating the biology of the tumor immune microenvironment (TiME) can provide vital insights into mechanisms of tumor progression. In this study, we developed a quantitative image processing platform to analyze sequential multiplexed IHC data from archival PDAC tissue resection specimens. A 27-plex marker panel was employed to simultaneously phenotype cell populations and their functional states, followed by a computational workflow to interrogate the immune contextures of the TiME in search of potential biomarkers. The PDAC TiME reflected a low-immunogenic ecosystem with both high intratumoral and intertumoral heterogeneity. Spatial analysis revealed that the relative distance between IL10+ myelomonocytes, PD-1+ CD4+ T cells, and granzyme B+ CD8+ T cells correlated significantly with survival, from which a spatial proximity signature termed imRS was derived that correlated with PDAC patient survival. Furthermore, spatial enrichment of CD8+ T cells in lymphoid aggregates was also linked to improved survival. Altogether, these findings indicate that thePDAC TiME, generally considered immuno-dormant or immunosuppressive, is a spatially nuanced ecosystem orchestrated by ordered immune hierarchies. This new understanding of spatial complexity may guide novel treatment strategies for PDAC.
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U2 - 10.1158/0008-5472.CAN-22-1190
DO - 10.1158/0008-5472.CAN-22-1190
M3 - Article
C2 - 36112643
AN - SCOPUS:85143198671
SN - 0008-5472
VL - 82
SP - 4359
EP - 4372
JO - Cancer Research
JF - Cancer Research
IS - 23
ER -