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Novel N-amidinopiperidine-based proteasome inhibitor preserves dendritic cell functionality and rescues their Th1-polarizing capacity in Ramos-conditioned tumor environment

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Abstract

The tumor microenvironment represents a burden that hampers the proper activation of immune cells, including the dendritic cells (DCs). It is, therefore, desired that the important characteristics of a given anticancer drug candidate be seen as consisting not solely of its antitumor properties, but that it also lacks potential side effects that could additionally constrain the development and function of immune cells associated with tumor immunity. We have previously identified compounds with a N-amidinopiperidine scaffold that selectively induce apoptosis in Burkitt’s lymphoma cells through proteasome inhibition. Here, we demonstrate that SPI-15 affected neither the viability of DCs nor their differentiation. In addition, the compound had no significant effect on their cytokine secretion or allostimulatory capacity. Moreover, DC functionality in the context of tumor microenvironment was also unaffected, as demonstrated by experiments performed on DCs differentiated in Ramos-conditioned media in the presence or absence of SPI-15. The cytokine profile and functional assays revealed that SPI-15 rescues DC differentiation from the immunosuppressive environment produced by Ramos cells; this was seen by their reacquired ability to induce IFN-γ-secretion from naïve CD4+CD45RA+ T cells and the consequently induced Th1-effector differentiation. Herein, we present novel characteristics of an N-amidinopiperidine-based protease inhibitor whose anticancer properties are not associated with the immunosuppression of DCs. We propose future studies toward the design of structurally similar compounds with the aim of developing potent anticancer drugs with minimal negative effects on crucial factors involved in tumor immunity.

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Abbreviations

CCR7:

C–C chemokine receptor type 7

DCs:

Dendritic cell

DC-SIGN:

Dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin

HLA-DR:

Human leukocyte antigen D-related

IDO:

Indoleamine-2,3-dioxygenase

LPS:

Lipopolysaccharide

MHC:

Major histocompatibility complex

MLR:

Mixed lymphocyte reaction

MSR-1:

Macrophage scavenger receptor 1

NfκB:

Nuclear factor κB

PRRs:

Pattern recognition receptors

SPI-15:

Serine protease inhibitor 15

TCR:

T cell receptor

TGF-β:

Transforming growth factor β

TLR:

Toll-like receptor

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Conflict of interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Blood Transfusion Centre of Slovenia, Šlajmerjeva 6, 1000, Ljubljana, Slovenia

    Urban Švajger

  2. Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000, Ljubljana, Slovenia

    Martina Gobec, Aleš Obreza & Irena Mlinarič-Raščan

Authors
  1. Urban Švajger
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  2. Martina Gobec
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  3. Aleš Obreza
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  4. Irena Mlinarič-Raščan
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Corresponding author

Correspondence to Irena Mlinarič-Raščan.

Additional information

Urban Švajger and Martina Gobec have contributed equally to this work.

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Švajger, U., Gobec, M., Obreza, A. et al. Novel N-amidinopiperidine-based proteasome inhibitor preserves dendritic cell functionality and rescues their Th1-polarizing capacity in Ramos-conditioned tumor environment. Cancer Immunol Immunother 64, 15–27 (2015). https://doi.org/10.1007/s00262-014-1608-x

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  • DOI: https://doi.org/10.1007/s00262-014-1608-x

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