Clusterin protects mature dendritic cells from reactive oxygen species mediated cell death

ABSTRACT

Dendritic cells (DCs) play a key role in the induction of the adaptive immune response. They capture antigens in peripheral tissues and prime naïve T lymphocytes, triggering the adaptive immune response. In the course of inflammatory processes DCs face stressful conditions including hypoxia, low pH and high concentrations of reactive oxygen species (ROS), among others. How DCs survive under these adverse conditions remain poorly understood. Clusterin is a protein highly expressed by tumors and usually associated with bad prognosis. It promotes cancer cell survival by different mechanisms such as apoptosis inhibition and promotion of autophagy. Here, we show that, upon maturation, human monocyte-derived DCs (MoDCs) up-regulate clusterin expression. Clusterin protects MoDCs from ROS-mediated toxicity, enhancing DC survival and promoting their ability to induce T cell activation. In line with these results, we found that clusterin is expressed by a population of mature LAMP3+ DCs, called mregDCs, but not by immature DCs in human cancer. The expression of clusterin by intratumoral DCs was shown to be associated with a transcriptomic profile indicative of cellular response to stress. These results uncover an important role for clusterin in DC physiology.

KEYWORDS:

• Cancer
• clusterin
• dendritic cells
• mregDC
• Ros

Acknowledgments

We deeply thank Matías Ostrowski and Federico Remes Lenicov for their technical assistance and scientific discussions.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

All relevant data is contained within the article: The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/2162402X.2023.2294564

Additional information

Funding

This work was supported by grants from the Agencia Nacional de Promoción Científica y Tecnológica, Argentina (PICT 2020/01829) and CONICET PIP 2021-2023 11220200102285CO to J.S.; Universidad de Buenos Aires (UBA) (UBACyT 20020130100446 BA) to J.G.