title: Tenascin-C Protects Cancer Stem-like Cells from Immune Surveillance by Arresting T-cell Activation.
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 cytokine 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.
authors: Division of Immunology, Transplantation and Infectious Diseases, Cellular Immunology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors: Elena
authors: E
authors: Jachetti
authors: Division of Immunology, Transplantation and Infectious Diseases, Cellular Immunology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy. Università Vita-Salute San Raffaele, Milan, Italy.
authors: Sara
authors: S
authors: Caputo
authors: Division of Regenerative Medicine, Neural Stem Cell Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors: Stefania
authors: S
authors: Mazzoleni
authors: Division of Immunology, Transplantation and Infectious Diseases, Cellular Immunology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors: Chiara Svetlana
authors: CS
authors: Brambillasca
authors: Division of Immunology, Transplantation and Infectious Diseases, Cellular Immunology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors: Sara Martina
authors: SM
authors: Parigi
authors: Division of Immunology, Transplantation and Infectious Diseases, Cellular Immunology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors: Matteo
authors: M
authors: Grioni
authors: Crs4, Biomedicine Sector, Scientific Park of Sardinia, Pula, Cagliari, Italy.
authors: Ignazio Stefano
authors: IS
authors: Piras
authors: Mass Spectrometry Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors: Umberto
authors: U
authors: Restuccia
authors: Division of Immunology, Transplantation and Infectious Diseases, Cellular Immunology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy. Mass Spectrometry Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors: Arianna
authors: A
authors: Calcinotto
authors: Unità Operativa Anatomia Patologica, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors: Massimo
authors: M
authors: Freschi
authors: Mass Spectrometry Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors: Angela
authors: A
authors: Bachi
authors: Division of Regenerative Medicine, Neural Stem Cell Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors: Rossella
authors: R
authors: Galli
authors: Division of Immunology, Transplantation and Infectious Diseases, Cellular Immunology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy. bellone.matteo@hsr.it.
authors: Matteo
authors: M
authors: Bellone
mesh_terms: D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D006801:Humans; D039081:Integrin alpha5beta1 / Q000378:metabolism; D008207:Lymphatic Metastasis; D008213:Lymphocyte Activation; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014411:Neoplastic Stem Cells / Q000276:immunology*; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000473:pathology; D022502:Stress Fibers / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D019063:Tenascin / Q000502:physiology*; D014407:Tumor Cells, Cultured; D019139:Tumor Escape
chemical_list: D039081:Integrin alpha5beta1; D019063:Tenascin