Pomalidomide alters pancreatic macrophage populations to generate an immune-responsive environment at precancerous and cancerous lesions

Ligia I. Bastea, Geou Yarh Liou, Veethika Pandey, Alicia K. Fleming, Christina A. Von Roemeling, Heike Doeppler, Zhimin Li, Yushi Qiu, Brandy Edenfield, John A III Copland, Han W Tun, Peter Storz

Research output: Contribution to journalArticle

Abstract

During development of pancreatic cancer, alternatively activated macrophages contribute to fibrogenesis, pancreatic intraepithelial neoplasia (PanIN) lesion growth, and generation of an immunosuppressive environment. Here, we show that the immunomodulatory agent pomalidomide depletes pancreatic lesion areas of alternatively activated macrophage populations. Pomalidomide treatment resulted in downregulation of interferon regulatory factor 4, a transcription factor for M2 macrophage polarization. Pomalidomide-induced absence of alternatively activated macrophages led to a decrease in fibrosis at PanIN lesions and in syngeneic tumors; this was due to generation of an inflammatory, immune-responsive environment with increased expression of IL1α and presence of activated (IFNγ-positive) CD4 + and CD8 + T-cell populations. Our results indicate that pomalidomide could be used to decrease fibrogenesis in pancreatic cancer and may be ideal as a combination treatment with chemotherapeutic drugs or other immunotherapies. Significance: These findings reveal new insights into how macrophage populations within the pancreatic cancer microenvironment can be modulated, providing the means to turn the microenvironment from immunosuppressive to immune-responsive.

Original languageEnglish (US)
Pages (from-to)1535-1548
Number of pages14
JournalCancer Research
Volume79
Issue number7
DOIs
StatePublished - Apr 1 2019

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Macrophages
Pancreatic Neoplasms
Population
Immunosuppressive Agents
Neoplasms
Tumor Microenvironment
Immunotherapy
Fibrosis
Transcription Factors
Down-Regulation
pomalidomide
T-Lymphocytes
Therapeutics
Growth
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Pomalidomide alters pancreatic macrophage populations to generate an immune-responsive environment at precancerous and cancerous lesions. / Bastea, Ligia I.; Liou, Geou Yarh; Pandey, Veethika; Fleming, Alicia K.; Von Roemeling, Christina A.; Doeppler, Heike; Li, Zhimin; Qiu, Yushi; Edenfield, Brandy; Copland, John A III; Tun, Han W; Storz, Peter.

In: Cancer Research, Vol. 79, No. 7, 01.04.2019, p. 1535-1548.

Research output: Contribution to journalArticle

Bastea, Ligia I. ; Liou, Geou Yarh ; Pandey, Veethika ; Fleming, Alicia K. ; Von Roemeling, Christina A. ; Doeppler, Heike ; Li, Zhimin ; Qiu, Yushi ; Edenfield, Brandy ; Copland, John A III ; Tun, Han W ; Storz, Peter. / Pomalidomide alters pancreatic macrophage populations to generate an immune-responsive environment at precancerous and cancerous lesions. In: Cancer Research. 2019 ; Vol. 79, No. 7. pp. 1535-1548.
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