Description
Correlations Between Smad4 status and Leukocyte Complexity in Human Pancreatic Cancer
Shannon M. Liudahl1, Takahiro Tsujikawa1, Jonathan A. Nowak3, Annacarolina Da Sliva3, Vicente Morales-Oyarvide3, Lauren K. Brais3, Marisa W. Welch3, Shamilene Sivagnanam2, Gina Choe1, Teresa Beechwood1, Young Hwan Chang2, Brian M. Wolpin3, Lisa M. Coussens1
1Department of Cell, Developmental & Cancer Biology, 2Program in Computational Biology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR USA; 3Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA USA
Genetic deletion or inactivating mutation of the tumor suppressor DPC4/Smad4 occurs in approximately 50% of pancreatic ductal adenocarcinomas (PDAs) and is associated with higher incidence of distant metastasis and poorer disease-free and overall survival as compared to PDAs maintaining Smad4 expression. Understanding how SMAD4 status may impact the immune microenvironments of PDAs is important, as SMAD4-regulated gene expression programs have been implicated in regulating leukocyte functionality. To thoroughly examine the relationship between SMAD4 status in PDAs and local immune responses, we employed quantitative multiplex immunohistochemistry to comprehensively examine immune cell composition and functional effector status of primary human PDAs of known Smad4 status, with the goal of revealing immune features and biomarkers to improve patient stratification for therapy. Preliminary results from these studies have revealed differences in presence of intratumoral T regulatory cells and CD8+ T cells expressing markers of exhaustion in Smad4- tumors, supporting the hypothesis that Smad4 loss may be correlated with increased intratumoral abundance of immunosuppressive leukocyte populations and dysfunctional CD8+ T cells. To be presented will be data examining myeloid and lymphoid composition, as well as functional status of infiltrating T cells, correlated with SMAD4-status and patient outcomes.
The authors acknowledge support from a Stand Up to Cancer - Lustgarten Foundation Pancreatic Cancer Convergence Dream Team Translational Research Grant, the Knight Cancer Institute, and the OHSU Brenden-Colson Center for Pancreatic Care (LMC), and the Hale Center for Pancreatic Cancer Research at Dana-Farber Cancer Institute (BMW)