Abstract PR-001: Neoadjuvant therapy is associated with altered composition of immune cell infiltration and an anti-tumorigenic microenvironment in resected pancreatic cancer

Background: Neoadjuvant therapy (neoTX) may improve survival for patients with resectable or borderline resectable pancreatic ductal adenocarcinoma (PDAC). However, the impact of neoTX on the tumor immune microenvironment is incompletely understood, hampering efforts to identify optimal treatment combinations and predictive markers to guide patient selection. Design: We employed digital image analysis and three multiplex immunofluorescence (mIF) assays, comprising 15 immune cell markers, to identify T cell subpopulations, macrophage polarization and myeloid cell subpopulations in primary resected PDAC. A multi-institution cohort of untreated tumors (n=299) was analyzed to characterize the baseline tumor immune microenvironment, while resected tumors after FOLFIRINOX-based neoTX (n=36) or upfront surgery (n=30) were analyzed to identify immune microenvironmental change due to neoTX. Multivariable Cox proportional hazard regression models were used to assess associations with patient outcomes. Results: Macrophages, T lymphocytes, and granulocytes were all abundant in the previously-untreated PDAC microenvironment, yet their densities exhibited substantial heterogeneity across patient tumors. In the untreated multi-institutional cohort, higher CD3+ T cell density was associated with longer disease-free survival (DFS) and overall survival (OS), while M2-polarized macrophages and CD15+ARG1+ immunosuppressive granulocytes were associated with shorter survival times. In particular, a higher ratio of CD3+CD8+ T cells to CD15+ARG1+ immunosuppressive granulocytes was associated with longer DFS (Q4 vs. Q1 HR 0.46, Ptrend=0.002) and OS (Q4 vs. Q1 HR 0.70, Ptrend=0.02). While neoTX did not alter overall CD3+ density, it increased the relative proportion of CD3+CD8+ cells, resulting in a lower CD4/CD8 ratio (p Citation Format: Andressa Dias Costa, Sara Vayrynen, Akhil Chawla, Jinming Zhang, Juha P. Vayrynen, Mai Chan Lau, Hannah L. Williams, Chen Yuan, Vicente Morales-Oyarvide, Douglas A. Rubinson, Thomas E. Clancy, Lauren K. Brais, Emma Reilly, Margaret M. Kozak, David C. Linehan, Richard F. Dunne, Daniel T. Chang, Aram F. Hezel, Albert C. Koong, Andrew J. Aguirre, Brian M. Wolpin, Jonathan A. Nowak. Neoadjuvant therapy is associated with altered composition of immune cell infiltration and an anti-tumorigenic microenvironment in resected pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PR-001.