Tenascin-C protects cancer stem-like cells from immune surveillance by arresting T-cell activation

Elena Jachetti, Sara Caputo, Stefania Mazzoleni, Chiara Svetlana Brambillasca, Sara Martina Parigi, Matteo Grioni, Ignazio Stefano Piras, Umberto Restuccia, Arianna Calcinotto, Massimo Freschi, Angela Bachi, Rossella Galli, Matteo Bellone

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Precociously disseminated cancer cells may seed quiescent sites of future metastasis if they can protect themselves from immune surveillance. However, there is little knowledge about how such sites might be achieved. Here, we present evidence that prostate cancer stem-like cells (CSC) can be found in histopathologically negative prostate draining lymph nodes (PDLN) in mice harboring oncogene-driven prostate intraepithelial neoplasia (mPIN). PDLN-derived CSCs were phenotypically and functionally identical to CSC obtained from mPIN lesions, but distinct from CSCs obtained from frank prostate tumors. CSC derived from either PDLN or mPIN used the extracellular matrix protein Tenascin-C (TNC) to inhibit T-cell receptor-dependent T-cell activation, proliferation, and cyto-kine production. Mechanistically, TNC interacted with α5β1 integrin on the cell surface of T cells, inhibiting reorganization of the actin-based cytoskeleton therein required for proper T-cell activation. CSC from both PDLN and mPIN lesions also expressed CXCR4 and migrated in response to its ligand CXCL12, which was overexpressed in PDLN upon mPIN development. CXCR4 was critical for the development of PDLN-derived CSC, as in vivo administration of CXCR4 inhibitors prevented establishment in PDLN of an immunosuppressive microenvironment. Taken together, our work establishes a pivotal role for TNC in tuning the local immune response to establish equilibrium between disseminated nodal CSC and the immune system.

Original languageEnglish
Pages (from-to)2095-2108
Number of pages14
JournalCancer Research
Volume75
Issue number10
DOIs
Publication statusPublished - May 15 2015

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Tenascin
Neoplastic Stem Cells
Prostate
T-Lymphocytes
Lymph Nodes
Neoplasms
Extracellular Matrix Proteins
Immunosuppressive Agents
T-Cell Antigen Receptor
Protein C
Actin Cytoskeleton
Oncogenes
Integrins
Immune System
Prostatic Neoplasms
Seeds
Cell Proliferation
Neoplasm Metastasis
Ligands

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Jachetti, E., Caputo, S., Mazzoleni, S., Brambillasca, C. S., Parigi, S. M., Grioni, M., ... Bellone, M. (2015). Tenascin-C protects cancer stem-like cells from immune surveillance by arresting T-cell activation. Cancer Research, 75(10), 2095-2108. https://doi.org/10.1158/0008-5472.CAN-14-2346

Tenascin-C protects cancer stem-like cells from immune surveillance by arresting T-cell activation. / Jachetti, Elena; Caputo, Sara; Mazzoleni, Stefania; Brambillasca, Chiara Svetlana; Parigi, Sara Martina; Grioni, Matteo; Piras, Ignazio Stefano; Restuccia, Umberto; Calcinotto, Arianna; Freschi, Massimo; Bachi, Angela; Galli, Rossella; Bellone, Matteo.

In: Cancer Research, Vol. 75, No. 10, 15.05.2015, p. 2095-2108.

Research output: Contribution to journalArticle

Jachetti, E, Caputo, S, Mazzoleni, S, Brambillasca, CS, Parigi, SM, Grioni, M, Piras, IS, Restuccia, U, Calcinotto, A, Freschi, M, Bachi, A, Galli, R & Bellone, M 2015, 'Tenascin-C protects cancer stem-like cells from immune surveillance by arresting T-cell activation', Cancer Research, vol. 75, no. 10, pp. 2095-2108. https://doi.org/10.1158/0008-5472.CAN-14-2346
Jachetti E, Caputo S, Mazzoleni S, Brambillasca CS, Parigi SM, Grioni M et al. Tenascin-C protects cancer stem-like cells from immune surveillance by arresting T-cell activation. Cancer Research. 2015 May 15;75(10):2095-2108. https://doi.org/10.1158/0008-5472.CAN-14-2346
Jachetti, Elena ; Caputo, Sara ; Mazzoleni, Stefania ; Brambillasca, Chiara Svetlana ; Parigi, Sara Martina ; Grioni, Matteo ; Piras, Ignazio Stefano ; Restuccia, Umberto ; Calcinotto, Arianna ; Freschi, Massimo ; Bachi, Angela ; Galli, Rossella ; Bellone, Matteo. / Tenascin-C protects cancer stem-like cells from immune surveillance by arresting T-cell activation. In: Cancer Research. 2015 ; Vol. 75, No. 10. pp. 2095-2108.
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