title: Adaptive immune contexture at the tumour site and downmodulation of circulating myeloid-derived suppressor cells in the response of solitary fibrous tumour patients to anti-angiogenic therapy.
abstract: BACKGROUND
  Host immunity is emerging as a key player in the prognosis and response to treatment of cancer patients. However, the impact of the immune system and its modulation by therapies are unknown in rare soft tissue sarcomas such as solitary fibrous tumours (SFTs), whose management in the advanced forms includes anti-angiogenic therapy. Here, we studied the in situ and systemic immune status of advanced SFT patients and the effects of sunitinib malate (SM) in association with the clinical efficacy.
  
  
  METHODS
  Immune contexture of SFTs was assessed by immunohistochemistry in lesions from untreated or SM-treated patients. Frequency of circulating myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs) and T-cell functions was assessed ex vivo in SFT patients prior and during anti-angiogenic therapy. Patients with long-term tumour control were included to correlate immune profiles and clinical responses.
  
  
  RESULTS
  Anti-angiogenic naïve SFT lesions were heavily infiltrated by CD163(+)CD14(+)CD68(-) and CD163(+)CD14(-)CD68(-) myeloid cells but devoid of T cells. Conversely, post-SM tumours acquired a new subset of CD68(+)CD14(+) myeloid cells and displayed traits of an on-going adaptive immunity, strongly enriched in activated CD8(+) and CD4(+) T cells. These changes at the tumour site paralleled the alleviation of systemic immunosuppression and the drop in the frequency of circulating monocytic MDSCs (mMDSCs) and granulocytic MDSCs (gMDSCs). Rebound in the number of mMDSCs, but not of gMDSCs occurred at disease progression, and a reduced percentages of mMDSCs, comparable to those found in healthy donors (HDs), endured only in the SM-responsive patients.
  
  
  CONCLUSIONS
  The immune contexture of SFT patients is heavily involved in anti-angiogenic therapy and it could be exploited to achieve more durable disease control through immune-based combination strategies.
authors.affiliation: 1] Unit of Immunotherapy of Human Tumours, Department of Experimental Oncology and Molecular Medicine, Via G. Venezian 1, Milan 20133, Italy [2] Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, Milan 20133, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Tazzari
authors.affiliation: 1] Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, Milan 20133, Italy [2] Laboratory of Experimental Molecular Pathology, Department of Diagnostic Pathology and Laboratory, Via G. Venezian 1, Milan 20133, Italy.
authors.forename: T
authors.initials: T
authors.lastname: Negri
authors.affiliation: 1] Unit of Immunotherapy of Human Tumours, Department of Experimental Oncology and Molecular Medicine, Via G. Venezian 1, Milan 20133, Italy [2] Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, Milan 20133, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Rini
authors.affiliation: Consorzio MIA (Microscopy and Image Analysis), University of Milano-Bicocca, Via G. Venezian 1, Milan 20133, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Vergani
authors.affiliation: 1] Unit of Immunotherapy of Human Tumours, Department of Experimental Oncology and Molecular Medicine, Via G. Venezian 1, Milan 20133, Italy [2] Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, Milan 20133, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Huber
authors.affiliation: Consorzio MIA (Microscopy and Image Analysis), University of Milano-Bicocca, Via G. Venezian 1, Milan 20133, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Villa
authors.affiliation: 1] Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, Milan 20133, Italy [2] Laboratory of Experimental Molecular Pathology, Department of Diagnostic Pathology and Laboratory, Via G. Venezian 1, Milan 20133, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Dagrada
authors.affiliation: 1] Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, Milan 20133, Italy [2] Department of Surgery, Via G. Venezian 1, Milan 20133, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Colombo
authors.affiliation: 1] Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, Milan 20133, Italy [2] Department of Surgery, Via G. Venezian 1, Milan 20133, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Fiore
authors.affiliation: 1] Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, Milan 20133, Italy [2] Department of Surgery, Via G. Venezian 1, Milan 20133, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Gronchi
authors.affiliation: 1] Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, Milan 20133, Italy [2] Adult Sarcoma Medical Oncology Unit, Department of Cancer Medicine, Via G. Venezian 1, Milan 20133, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Stacchiotti
authors.affiliation: 1] Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, Milan 20133, Italy [2] Adult Sarcoma Medical Oncology Unit, Department of Cancer Medicine, Via G. Venezian 1, Milan 20133, Italy.
authors.forename: P G
authors.initials: PG
authors.lastname: Casali
authors.affiliation: 1] Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, Milan 20133, Italy [2] Laboratory of Experimental Molecular Pathology, Department of Diagnostic Pathology and Laboratory, Via G. Venezian 1, Milan 20133, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Pilotti
authors.affiliation: 1] Unit of Immunotherapy of Human Tumours, Department of Experimental Oncology and Molecular Medicine, Via G. Venezian 1, Milan 20133, Italy [2] Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, Milan 20133, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Rivoltini
authors.affiliation: 1] Unit of Immunotherapy of Human Tumours, Department of Experimental Oncology and Molecular Medicine, Via G. Venezian 1, Milan 20133, Italy [2] Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, Milan 20133, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Castelli
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects*; D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D008297:Male; D008875:Middle Aged; D023461:Myeloid Progenitor Cells / Q000187:drug effects / Q000276:immunology*; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D054364:Solitary Fibrous Tumors / Q000097:blood / Q000188:drug therapy / Q000276:immunology*; D000077210:Sunitinib; D016896:Treatment Outcome; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology
chemical_list: D020533:Angiogenesis Inhibitors; D007211:Indoles; D011758:Pyrroles; D000077210:Sunitinib
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