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Cholesterol metabolites and tumor microenvironment: the road towards clinical translation

  • Focussed Research Review
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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Targeting the tumor microenvironment focusing on immune cells has recently become a standard of care for some tumors. Indeed, antibodies blocking immune checkpoints (e.g., anti-CTLA-4 and anti-PD1 mAbs) have been approved by regulatory agencies for the treatment of some solid tumors based upon successes in many clinical trials. Although tumor metabolism has always attracted the attention of tumor biologists, only recently have oncologists renewed their interest in this field of tumor biology research. This has highlighted the possibility to pharmacologically target rate-limiting enzymes along key metabolic pathways of tumor cells, such as lipogenesis and aerobic glycolysis. Altered tumor metabolism has also been shown to influence the functionality of the tumor microenvironment as a whole, particularly the immune cell component of thereof. Cholesterol, oxysterols and Liver X receptors (LXRs) have been investigated in different tumor models. Recent in vitro and in vivo results point to their involvement in tumor and immune cell biology, thus making the LXR/oxysterol axis a possible target for novel antitumor strategies. Indeed, the possibility to target both tumor cell metabolism (i.e., cholesterol metabolism) and tumor-infiltrating immune cell dysfunctions induced by oxysterols might result in a synergistic antitumor effect generating long-lasting memory responses. This review will focus on the role of cholesterol metabolism with particular emphasis on the role of the LXR/oxysterol axis in the tumor microenvironment, discussing mechanisms of action, pros and cons, and strategies to develop antitumor therapies based on the modulation of this axis.

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Abbreviations

ABC:

ATP-binding cassette

AIM/SPα:

Apoptosis inhibitor of macrophages

BRAF:

BRAF proto-oncogene, serine/threonine kinase

CCR:

Chemokine receptor

CTLA-4:

Cytotoxic T lymphocyte-associated protein 4

CXCR:

CXC chemokine receptor

DC:

Dendritic cell

ER:

Endoplasmic reticulum

HDL:

High-density lipoprotein

HMGCR:

Hydroxyl-methyl glutaryl-coenzyme A reductase

INSIG:

Insulin-induced gene

LDL:

Low-density lipoprotein

LDLR:

Low-density lipoprotein receptor

LXR:

Liver X receptor

mTOR:

Mammalian target of rapamycin

PD1:

Programmed cell death protein 1

RCT:

Reverse cholesterol transport

SCAP:

SREBP-cleavage activation protein

SREBP:

Sterol response element binding protein

SULT2B1b:

Sulfotransferase 2B1b

Th:

T helper cell

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Acknowledgments

This work was supported by the Italian Association for Cancer Research (AIRC) and by the Italian Ministry of Health (RF2009).

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Authors and Affiliations

  1. Unit of Immuno-Biotherapy of Melanoma and Solid Tumors, Division of Experimental Oncology, San Raffaele Scientific Institute, via Olgettina 58, Milan, Italy

    Laura Raccosta, Raffaella Fontana, Gianfranca Corna, Daniela Maggioni, Marta Moresco & Vincenzo Russo

  2. San Raffaele Vita-Salute University, via Olgettina 60, Milan, Italy

    Raffaella Fontana & Marta Moresco

Authors
  1. Laura Raccosta
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  2. Raffaella Fontana
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  3. Gianfranca Corna
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  4. Daniela Maggioni
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  5. Marta Moresco
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  6. Vincenzo Russo
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Corresponding author

Correspondence to Vincenzo Russo.

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The authors declare no conflict of interest.

Additional information

This paper is a Focussed Research Review based on a presentation given at the Twelfth Meeting of the Network Italiano per la Bioterapia dei Tumori (NIBIT) on Cancer Bio-Immunotherapy, held in Siena, Italy, 9th–11th October 2014. It is part of a series of Focussed Research Reviews and meeting report in Cancer Immunology, Immunotherapy.

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Raccosta, L., Fontana, R., Corna, G. et al. Cholesterol metabolites and tumor microenvironment: the road towards clinical translation. Cancer Immunol Immunother 65, 111–117 (2016). https://doi.org/10.1007/s00262-015-1779-0

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