(1) Dias Costa A (2) Väyrynen SA (3) Chawla A (4) Zhang J (5) Väyrynen JP (6) Lau MC (7) Williams HL (8) Yuan C (9) Morales-Oyarvide V (10) Elganainy D (11) Singh H (12) Cleary JM (13) Perez K (14) Ng K (15) Freed-Pastor W (16) Mancias JD (17) Dougan SK (18) Wang J (19) Rubinson DA (20) Dunne RF (21) Kozak MM (22) Brais L (23) Reilly E (24) Clancy T (25) Linehan DC (26) Chang DT (27) Hezel AF (28) Koong AC (29) Aguirre A (30) Wolpin BM (31) Nowak JA

Clinical Cancer Research

Visualized through multiplexed immunofluorescence, immune cells localized near tumor cells in PDAC tumors. Patterns of immune infiltration included granulocyte, macrophage, and T cell enrichment, the latter correlating with improved OS. Tumors treated with neoadjuvant FOLFIRINOX chemotherapy had increased densities of CD8+ T cells and M1 macrophages, and reduced ARG1+ granulocytes relative to those removed immediately with surgery. In addition, M1 macrophage proximity to tumor cells was increased in neoadjuvant-treated tumors, and correlated positively with OS and histological response.

Contributed by Alex Najibi

PURPOSE: Neoadjuvant chemotherapy is increasingly administered to patients with resectable or borderline resectable pancreatic ductal adenocarcinoma (PDAC), yet its impact on the tumor immune microenvironment is incompletely understood. EXPERIMENTAL DESIGN: We employed quantitative, spatially-resolved multiplex immunofluorescence and digital image analysis to identify T-cell subpopulations, macrophage polarization states and myeloid cell subpopulations in a multi-institution cohort of up-front resected primary tumors (n=299) and in a comparative set of resected tumors after FOLFIRINOX-based neoadjuvant therapy (n=36) or up-front surgery (n=30). Multivariable-adjusted Cox proportional hazards models were used to evaluate associations between the immune microenvironment and patient outcomes. RESULTS: In the multi-institutional resection cohort, immune cells exhibited substantial heterogeneity across patient tumors and were located predominantly in stromal regions. Unsupervised clustering using immune cell densities identified four main patterns of immune cell infiltration. One pattern, seen in 20% of tumors and characterized by abundant T cells (T cell-rich) and a paucity of immunosuppressive granulocytes and macrophages, was associated with improved patient survival. Neoadjuvant chemotherapy was associated with a higher CD8:CD4 ratio, greater M1:M2-polarized macrophage ratio, and reduced CD15+ARG1+ immunosuppressive granulocyte density. Within neoadjuvant-treated tumors, 64% showed a T-cell-rich pattern with low immunosuppressive granulocytes and macrophages. M1-polarized macrophages were located closer to tumor cells after neoadjuvant chemotherapy and colocalization of M1-polarized macrophages and tumor cells was associated with greater tumor pathologic response and improved patient survival. CONCLUSION: Neoadjuvant chemotherapy with FOLFIRINOX shifts the PDAC immune microenvironment towards an anti-tumorigenic state associated with improved patient survival.

Author Info: (1) Dana-Farber Cancer Institute, Boston, MA, United States. (2) Dana-Farber Cancer Institute, Boston, MA, United States. (3) Northwestern University, Chicago, Illinois, United Sta

Author Info: (1) Dana-Farber Cancer Institute, Boston, MA, United States. (2) Dana-Farber Cancer Institute, Boston, MA, United States. (3) Northwestern University, Chicago, Illinois, United States. (4) Dana-Farber Cancer Institute, Boston, MA, United States. (5) University of Oulu, Oulu, Finland. (6) Brigham and Women's Hospital, Boston, MA, United States. (7) Dana-Farber Cancer Institute, Boston, MA, United States. (8) Dana-Farber Cancer Institute, Boston, MA, United States. (9) Dana-Farber Cancer Institute, Boston, MA, United States. (10) Dana-Farber Cancer Institute, Boston, MA, United States. (11) Dana-Farber Cancer Institute, Boston, MA, United States. (12) Dana-Farber Cancer Institute, Boston, MA, United States. (13) Dana-Farber Cancer Institute, Boston, MA, United States. (14) Dana-Farber Cancer Institute, Boston, MA, United States. (15) Dana-Farber Cancer Institute, Boston, MA, United States. (16) Dana-Farber Cancer Institute, Boston, MA, United States. (17) Dana-Farber Cancer Institute, Boston, MA, United States. (18) Brigham and Women's Hospital, Boston, United States. (19) Dana-Farber Cancer Institute, Boston, MA, United States. (20) University of Rochester Medical Center, Rochester, NY, United States. (21) Stanford University School of Medicine, Palo Alto, CA, United States. (22) Dana-Farber Cancer Institute, Boston, MA, United States. (23) Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, United States. (24) Brigham and Women's Hospital, Boston, MA, United States. (25) University of Rochester, Rochester, NY, United States. (26) Stanford University, Stanford, CA, United States. (27) University of Rochester School of Medicine, Rochester, NY, United States. (28) The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (29) Dana-Farber Cancer Institute, Boston, MA, United States. (30) Dana-Farber/Harvard Cancer Center, Boston, MA, United States. (31) Brigham and Women's Hospital, Boston, MA, United States.

Citation: Clin Cancer Res 2022 Sep 21 Epub09/21/2022

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/36129461

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