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Lysosomal peptidases in innate immune cells: implications for cancer immunity

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Abstract

Cathepsins are lysosomal peptidases involved in intracellular protein catabolism as well as in various other physiological and pathological processes. Several members of the family, most notably cathepsins B, S, K and L, are frequently overexpressed in cancer and have been associated with remodeling of the proteins of the extracellular matrix, a process leading to tumor cell migration, invasion and metastasis. In addition, lysosomal cathepsins play a role in innate and adaptive immunity, regulation of antigen presentation, Toll-like receptor signaling, cytokine secretion, apoptosis, autophagy, differentiation, migration and cytotoxicity. In cancer, the cells of innate immunity, such as myeloid cells, are often subverted to the regulatory immunosuppressive phenotype. Most studies indicate that lysosomal cathepsins reinforce the pro-tumoral activity of myeloid-derived suppressor cells and tumor-associated macrophages as well as of neutrophils. On the other hand, in cytotoxic natural killer cells, tumor cells suppress lysosomal peptidases in their activation of perforin and granzymes, thus diminishing their killing ability. With multifaceted actions, lysosomal peptidases constitute an important regulatory mechanism for fine-tuning the anti-tumor immune response.

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Abbreviations

AEP:

Asparaginyl endopeptidase

Arp 2/3:

Actin-related proteins 2/3

COX2:

Cyclooxygenase 2

CTL:

Cytotoxic T lymphocytes

DC:

Dendritic cells

HLA-DM:

Human leukocyte antigen DM

HMGB1:

High-mobility group box 1

GILT:

Γ-interferon-inducible thiol reductase

ICAM-1:

Intercellular adhesion molecule 1

IRAK4:

IL-1 receptor-associated kinase 4

LFA-1:

Lymphocyte function-associated antigen 1

Mac-1:

Macrophage-1 antigen

MDSC:

Myeloid-derived suppressor cells

MHC II:

Major histocompatibility complex class II

NET:

Neutrophil extracellular traps

NK:

Natural killer

NOX2:

NADPH oxidase 2

PAR2:

Protease-activated receptor 2

SIRP α:

Signal regulatory protein α

STAT3:

Signal transducer and activator of transcription 3

TAM:

Tumor-associated macrophages

TLR:

Toll-like receptors

WASP:

Wiskott–Aldrich syndrome protein

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Acknowledgements

We sincerely thank Professor Roger H. Pain for critical reading of the manuscript.

Funding

This work was supported by the Grants P4-0127 and J4-8227 from the Research Agency of the Republic of Slovenia (to Janko Kos).

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Authors and Affiliations

  1. Department of Pharmaceutical Biology, Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000, Ljubljana, Slovenia

    Tanja Jakoš, Anja Pišlar, Urša Pečar Fonović & Janko Kos

  2. Department of Biotechnology, Jožef Stefan Institute, Ljubljana, Slovenia

    Janko Kos

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  1. Tanja Jakoš
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  2. Anja Pišlar
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  3. Urša Pečar Fonović
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  4. Janko Kos
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TJ drafted the manuscript and designed the figure. UPF, AP and JK finalized and complemented the manuscript.

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Correspondence to Janko Kos.

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Jakoš, T., Pišlar, A., Pečar Fonović, U. et al. Lysosomal peptidases in innate immune cells: implications for cancer immunity. Cancer Immunol Immunother 69, 275–283 (2020). https://doi.org/10.1007/s00262-019-02447-0

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