Addition of Losartan to FOLFIRINOX and Chemoradiation Reduces Immunosuppression-Associated Genes, Tregs, and FOXP3+ Cancer Cells in Locally Advanced Pancreatic Cancer-Reference-Cited by-同舟云学术

Addition of Losartan to FOLFIRINOX and Chemoradiation Reduces Immunosuppression-Associated Genes, Tregs, and FOXP3+ Cancer Cells in Locally Advanced Pancreatic Cancer

Published:2023-02-07 Issue:8 Volume:29 Page:1605-1619
ISSN:1078-0432
Container-title:Clinical Cancer Research
language:en
Short-container-title:

Author:

Boucher Yves¹^ORCID,Posada Jessica M.¹²^ORCID,Subudhi Sonu¹^ORCID,Kumar Ashwin S.¹³^ORCID,Rosario Spencer R.⁴⁵^ORCID,Gu Liqun¹^ORCID,Kumra Heena¹^ORCID,Mino-Kenudson Mari⁶^ORCID,Talele Nilesh P.¹^ORCID,Duda Dan G.¹^ORCID,Fukumura Dai¹^ORCID,Wo Jennifer Y.⁷^ORCID,Clark Jeffrey W.⁸^ORCID,Ryan David P.⁸^ORCID,Fernandez-Del Castillo Carlos⁹^ORCID,Hong Theodore S.⁷^ORCID,Pittet Mikael J.¹⁰¹¹¹²^ORCID,Jain Rakesh K.¹^ORCID

Affiliation:

1. 1Steele Laboratories of Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

2. 2Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.

3. 3Harvard–MIT Division of Health Sciences and Technology, Cambridge, Massachusetts.

4. 4Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York.

5. 5Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, New York.

6. 6Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

7. 7Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

8. 8Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

9. 9Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

10. 10Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.

11. 11Ludwig Institute for Cancer Research, Lausanne, Switzerland.

12. 12Agora Cancer Research Center, Lausanne, Switzerland.

Abstract

AbstractPurpose:Adding losartan (LOS) to FOLFIRINOX (FFX) chemotherapy followed by chemoradiation (CRT) resulted in 61% R0 surgical resection in our phase II trial in patients with locally advanced pancreatic cancer (LAPC). Here we identify potential mechanisms of benefit by assessing the effects of neoadjuvant LOS on the tumor microenvironment.Experimental Design:We performed a gene expression and immunofluorescence (IF) analysis using archived surgical samples from patients treated with LOS+FFX+CRT (NCT01821729), FFX+CRT (NCT01591733), or surgery upfront, without any neoadjuvant therapy. We also conducted a longitudinal analysis of multiple biomarkers in the plasma of treated patients.Results:In comparison with FFX+CRT, LOS+FFX+CRT downregulated immunosuppression and pro-invasion genes. Overall survival (OS) was associated with dendritic cell (DC) and antigen presentation genes for patients treated with FFX+CRT, and with immunosuppression and invasion genes or DC- and blood vessel–related genes for those treated with LOS+FFX+CRT. Furthermore, LOS induced specific changes in circulating levels of IL-8, sTie2, and TGF-β. IF revealed significantly less residual disease in lesions treated with LOS+FFX+CRT. Finally, patients with a complete/near complete pathologic response in the LOS+FFX+CRT–treated group had reduced CD4+FOXP3+ regulatory T cells (Tregs), fewer immunosuppressive FOXP3+ cancer cells (C-FOXP3), and increased CD8+ T cells in pancreatic ductal adenocarcinoma lesions.Conclusions:Adding LOS to FFX+CRT reduced pro-invasion and immunosuppression–related genes, which were associated with improved OS in patients with LAPC. Lesions from responders in the LOS+FFX+CRT–treated group had reduced Tregs, decreased C-FOXP3 and increased CD8+ T cells. These findings suggest that LOS may potentiate the benefit of FFX+CRT by reducing immunosuppression.

Funder

National Cancer Institute

National Institutes of Health

U.S. Department of Defense

Jane's Trust

Ludwig Institute for Cancer Research

National Foundation for Cancer Research

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

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