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Transfer of Manipulated Tumor-associated Neutrophils into Tumor-Bearing Mice to Study their Angiogenic Potential In Vivo
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Transfer of Manipulated Tumor-associated Neutrophils into Tumor-Bearing Mice to Study their Angiogenic Potential In Vivo

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Platelet-activating factor (PAF) promotes immunosuppressive neutrophil differentiation within tumors

Ankit Dahal1, Yeonsun Hong1, Jocelyn S Mathew1

  • 1Department of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, NY.

Proceedings of the National Academy of Sciences of the United States of America
|August 23, 2024
PubMed

Insights

Tumor cells release lipid mediators, like platelet-activating factor (PAF), that transform neutrophils into immunosuppressive myeloid-derived suppressor cells (MDSCs). This discovery offers a new target for cancer immunotherapy by blocking this lipid-driven differentiation pathway.

Area of Science:

  • Immunology
  • Cancer Biology
  • Molecular Medicine

Background:

  • Chronic inflammation in the tumor microenvironment (TME) promotes myeloid-derived suppressor cells (MDSCs), particularly polymorphonuclear (PMN)-MDSCs, which are neutrophils that suppress anti-cancer immunity.
  • The precise mechanisms driving neutrophil immunosuppression within the TME are not fully understood, hindering effective cancer immunotherapy development.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which neutrophils acquire immunosuppressive functions within the TME.
  • To identify specific tumor-derived factors responsible for inducing immunosuppressive phenotypes in neutrophils.

Main Methods:

  • In vitro co-culture of naive neutrophils with cancer cell supernatant.
  • Analysis of neutrophil phenotype, including arginase 1 (Arg1) and dcTrail-R1 expression, and CD8 T cell cytotoxicity assays.
  • Liquid chromatography-mass spectrometry (LC-MS) lipidomic analysis of cancer cell secretomes.
  • Correlation analysis of lysophosphatidylcholine acyltransferase 2 (LPCAT2) expression with patient survival in pancreatic ductal adenocarcinoma (PDAC) and other cancers.

Main Results:

  • Newly recruited neutrophils in the TME exhibit activated, motile, and immunosuppressive characteristics.
  • Incubating naive neutrophils with cancer cell supernatant in vitro successfully induced immunosuppressive phenotypes.
  • Cancer cell secretomes contain lipid mediators that drive neutrophil differentiation into immunosuppressive cells.
  • Platelet-activating factor (PAF) was identified as a key tumor-derived lipid mediator inducing neutrophil differentiation.
  • Lysophosphatidylcholine acyltransferase 2 (LPCAT2), an enzyme in PAF biosynthesis, is upregulated in PDAC and linked to poorer patient survival.

Conclusions:

  • Tumor-derived platelet-activating factor (PAF) is a critical lipid mediator driving the differentiation of immunosuppressive neutrophils (PMN-MDSCs) within the TME.
  • This lipid-driven mechanism represents a significant pathway for immune suppression in cancer.
  • Targeting PAF or its biosynthetic pathway presents a promising strategy for developing novel cancer immunotherapies.
Keywords:
CancerMDSCmyeloid cellsneutrophiltumor microenvironment

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