Neoadjuvant Chemotherapy Is Associated with Altered Immune Cell Infiltration and an Anti-Tumorigenic Microenvironment in Resected Pancreatic Cancer

Author:

Dias Costa Andressa1ORCID,Väyrynen Sara A.1ORCID,Chawla Akhil23ORCID,Zhang Jinming1ORCID,Väyrynen Juha P.145ORCID,Lau Mai Chan4ORCID,Williams Hannah L.1ORCID,Yuan Chen1ORCID,Morales-Oyarvide Vicente1ORCID,Elganainy Dalia1ORCID,Singh Harshabad1ORCID,Cleary James M.1ORCID,Perez Kimberly1ORCID,Ng Kimmie1ORCID,Freed-Pastor William1ORCID,Mancias Joseph D.6ORCID,Dougan Stephanie K.7ORCID,Wang Jiping8ORCID,Rubinson Douglas A.1ORCID,Dunne Richard F.9ORCID,Kozak Margaret M.10ORCID,Brais Lauren1ORCID,Reilly Emma1ORCID,Clancy Thomas8ORCID,Linehan David C.11ORCID,Chang Daniel T.10ORCID,Hezel Aram F.12ORCID,Koong Albert C.13ORCID,Aguirre Andrew J.114ORCID,Wolpin Brian M.1ORCID,Nowak Jonathan A.15ORCID

Affiliation:

1. 1Department of Medical Oncology, Dana–Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.

2. 2Department of Surgery, Northwestern Medicine Regional Medical Group, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

3. 3Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois.

4. 4Program in Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.

5. 5Cancer and Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital, and University of Oulu, Oulu, Finland.

6. 6Department of Radiation Oncology, Dana–Farber Cancer Institute and Brigham and Women's Hospital, Boston, Massachusetts.

7. 7Department of Cancer Immunology and Virology, Dana–Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.

8. 8Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.

9. 9Division of Hematology and Oncology, Department of Medicine, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York.

10. 10Department of Radiation Oncology, Stanford Cancer Institute, Stanford, California.

11. 11Department of General Surgery, University of Rochester Medical Center, Rochester, New York.

12. 12Department of Cell, Developmental & Cancer Biology, Oregon Health and Science University, Portland, Oregon.

13. 13Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

14. 14Broad Institute of MIT and Harvard, Cambridge, Massachusetts.

15. 15Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.

Abstract

Abstract 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, 72% 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. Conclusions: Neoadjuvant chemotherapy with FOLFIRINOX shifts the PDAC immune microenvironment toward an anti-tumorigenic state associated with improved patient survival.

Funder

Finish Cultural Foundation and Orion Research

Hale Family Center for Pancreatic Cancer Research

Lustgarten Foundation

National Institutes of Health

Pancreatic Cancer Action Network

Novartis

Bristol-Myers Squibb

Genocea

Doris Duke Charitable Foundation

Stand Up To Cancer

Noble Effort Fund

Wexler Family Fund

Promises for Purple

Bob Parsons Fund

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

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