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Downregulation of Membrane Trafficking Proteins and Lactate Conditioning Determine Loss of Dendritic Cell Function in

Nicoletta Caronni1, Francesca Simoncello1, Francesca Stafetta1

  • 1International Centre for Genetic Engineering and Biotechnology, Trieste, Italy.

Cancer Research
|January 25, 2018
PubMed

Insights

Tumor microenvironments suppress dendritic cell (DC) function in lung cancer by downregulating VAMP3 and inhibiting antigen presentation. Lactic acid impairs DC responses, hindering antitumor immunity.

Area of Science:

  • Immunology
  • Cancer Biology
  • Cellular Biology

Background:

  • Restoring antigen presentation by dendritic cells (DCs) is crucial for effective cancer immunotherapy.
  • Mechanisms of DC dysfunction within the tumor microenvironment are not fully understood, hindering targeted therapeutic development.

Purpose of the Study:

  • To investigate the mechanisms by which lung tumors subvert DC function and impair T-cell responses.
  • To identify specific factors within the tumor microenvironment responsible for DC suppression.

Main Methods:

  • Analysis of DCs from lung tumor tissues and DCs exposed to tumor-derived factors.
  • Assessment of DC response to endosomal and cytosolic sensor stimulation.
  • Evaluation of VAMP3 expression and its role in antigen presentation.
  • Investigation of lactic acid's impact on DC function and T-cell priming.

Main Results:

  • Tumor-conditioned DCs exhibit refractoriness to sensor stimulation and reduced IL12/IFN-I secretion.
  • Downregulation of VAMP3 in tumor-conditioned DCs impairs antigen cross-presentation.
  • Lactic acid in the tumor microenvironment inhibits type-I IFN signaling and DC cross-presentation.
  • Lactate-conditioned DCs fail to prime effective antitumor responses in vivo.

Conclusions:

  • Lung tumor microenvironments induce DC dysfunction through both cell-intrinsic and cell-extrinsic mechanisms.
  • Lactic acid is a key suppressive factor that impairs DC function and antigen presentation.
  • Understanding these mechanisms offers potential for novel therapeutic strategies to enhance cancer immunotherapy.

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