title: CD103 is a hallmark of tumor-infiltrating regulatory T cells.
abstract: Regulatory T cells (Treg) mediate tolerance towards self-antigens by suppression of innate and adaptive immunity. In cancer patients, tumor-infiltrating FoxP3+ Treg suppress local anti-tumor immune responses and are often associated with poor prognosis. Markers that are selectively expressed on tumor-infiltrating Treg may serve as targets for immunotherapy of cancer. Here we show that CD103, an integrin mediating lymphocyte retention in epithelial tissues, is expressed at high levels on tumor-infiltrating FoxP3+ Treg in several types of murine cancer. In the CT26 model of colon cancer up to 90% of the intratumoral FoxP3+ cells expressed CD103 compared to less than 20% in lymphoid organs. CD103+ Treg suppressed T effector cell activation more strongly than CD103(neg) Treg. Expression of CD103 on Treg closely correlated with intratumoral levels of transforming growth factor β (TGF-β) and could be induced in a TGF-β-dependent manner by tumor cell lines. In vivo, gene silencing of TGF-β reduced the frequency of CD103+ Treg, demonstrating that CD103 expression on tumor-infiltrating Treg is driven by intratumoral TGF-β. Functional blockade of CD103 using a monoclonal antibody did however not reduce the number of intratumoral Treg, indicating that CD103 is not involved in homing or retention of FoxP3+ cells in the tumor tissue. In conclusion, expression of CD103 is a hallmark of Treg that infiltrate TGF-β-secreting tumors. CD103 thus represents an interesting target for selective depletion of tumor-infiltrating Treg, a strategy that may help to improve anti-cancer therapy.
authors.affiliation: Center of Integrated Protein Science Munich, Division of Clinical Pharmacology, Ziemssenstrasse 1, 80336 Munich, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Anz
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Mueller
authors.forename: Michaela
authors.initials: M
authors.lastname: Golic
authors.forename: Wolfgang G
authors.initials: WG
authors.lastname: Kunz
authors.forename: Moritz
authors.initials: M
authors.lastname: Rapp
authors.forename: Viktor H
authors.initials: VH
authors.lastname: Koelzer
authors.forename: Jonathan
authors.initials: J
authors.lastname: Ellermeier
authors.forename: Joachim W
authors.initials: JW
authors.lastname: Ellwart
authors.forename: Max
authors.initials: M
authors.lastname: Schnurr
authors.forename: Carole
authors.initials: C
authors.lastname: Bourquin
authors.forename: Stefan
authors.initials: S
authors.lastname: Endres
mesh_terms: D000818:Animals; D015703:Antigens, CD; D045744:Cell Line, Tumor; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D039001:Integrin alpha Chains; D016246:Lymphocytes, Tumor-Infiltrating / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D050378:T-Lymphocytes, Regulatory; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D039001:Integrin alpha Chains; D016212:Transforming Growth Factor beta; C091367:alpha E integrins