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The administration of drugs inhibiting cholesterol/oxysterol synthesis is safe and increases the efficacy of immunotherapeutic regimens in tumor-bearing mice

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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Tumor-derived metabolites dampen tumor-infiltrating immune cells and antitumor immune responses. Among the various metabolites produced by tumors, we recently showed that cholesterol oxidized products, namely oxysterols, favor tumor growth through the inhibition of DC migration toward lymphoid organs and by promoting the recruitment of pro-tumor neutrophils within the tumor microenvironment. Here, we tested different drugs capable of blocking cholesterol/oxysterol formation. In particular, we tested efficacy and safety of different administration schedules, and of immunotherapy-based combination of a class of compounds, namely zaragozic acids, which inhibit cholesterol pathway downstream of mevalonate formation, thus leaving intact the formation of the isoprenoids, which are required for the maturation of proteins involved in the immune cell function. We show that zaragozic acids inhibit the in vivo growth of the RMA lymphoma and the Lewis lung carcinoma (LLC) without inducing side effects. Tumor growth inhibition requires an intact immune system, as immunodeficient tumor-bearing mice do not respond to zaragozic acid treatment. Of note, the effect of zaragozic acids is accompanied by a marked reduction in the LXR target genes Abcg1, Mertk, Scd1 and Srebp-1c in the tumor microenvironment. On the other hand, zoledronate, which blocks also isoprenoid formation, did not control the LLC tumor growth. Finally, we show that zaragozic acids potentiate the antitumor effects of active and adoptive immunotherapy, significantly prolonging the overall survival of tumor-bearing mice treated with the combo zaragozic acids and TAA-loaded DCs. This study identifies zaragozic acids as new antitumor compounds exploitable for the treatment of cancer patients.

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Abbreviations

ABCG1:

ATP-binding cassette G1

ΔLNGFr:

Low-affinity nerve growth factor receptor

HMG-CoA:

Hydroxymethylglutaryl-coenzyme A reductase

LXR:

Liver X receptor

MERTK:

MER poroto-oncogene tyrosine kinase

MMP-9:

Matrix metalloproteinase 9

MUT-1:

Mutated connexin 37 gap-junction protein-derived peptide

OVA-CSM:

OVA-cell surface marker

SCD1:

Stearoyl-CoA desaturase-1

SEM:

Standard error of mean

SREBP:

Sterol response element binding protein

VEGF:

Vascular endothelial growth factor

ZA:

Zaragozic acid(s)

ZO:

Zoledronate

VAX:

Vaccination

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Acknowledgments

This work was supported by the Italian Association for Cancer Research (AIRC) and the Italian Ministry of Health (RF2009). C. Bordignon and C. Traversari are employees of Molmed S.p.A.

Author information

Author notes

  1. Claudia Lanterna

    Present address: MolMed S.p.A., Milan, Italy

  2. Andrea Musumeci

    Present address: Institute for Immunology, Munich, Germany

Authors and Affiliations

  1. Immuno-Biotherapy of Melanoma and Solid Tumors Unit, Division of Experimental Oncology, IRCCS Scientific Institute San Raffaele, Via Olgettina 58, 20132, Milan, Italy

    Claudia Lanterna, Andrea Musumeci, Laura Raccosta, Gianfranca Corna, Marta Moresco, Daniela Maggioni, Raffaella Fontana & Vincenzo Russo

  2. Department of Pathology, IRCCS Scientific Institute San Raffaele, Milan, Italy

    Claudio Doglioni

  3. Università Vita-Salute San Raffaele, Milan, Italy

    Claudio Doglioni & Claudio Bordignon

  4. MolMed S.p.A., Milan, Italy

    Claudio Bordignon & Catia Traversari

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  1. Claudia Lanterna
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Correspondence to Vincenzo Russo.

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Lanterna, C., Musumeci, A., Raccosta, L. et al. The administration of drugs inhibiting cholesterol/oxysterol synthesis is safe and increases the efficacy of immunotherapeutic regimens in tumor-bearing mice. Cancer Immunol Immunother 65, 1303–1315 (2016). https://doi.org/10.1007/s00262-016-1884-8

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