title: Tumor-infiltrating HLA-matched CD4(+) T cells retargeted against Hodgkin and Reed-Sternberg cells.
abstract: Hodgkin lymphoma (HL) presents with a unique histologic pattern. Pathognomonic Hodgkin and Reed-Sternberg (HRS) cells usually account for less than 1% of the tumor and are embedded in a reactive infiltrate mainly comprised of CD4(+) T cells. HRS cells induce an immunosuppressive microenvironment and thereby escape antitumor immunity. To investigate the impact of interactions between HRS cells and T cells, we performed long-term co-culture studies that were further translated into a xenograft model. Surprisingly, we revealed a strong antitumor potential of allogeneic CD4(+) T cells against HL cell lines. HRS and CD4(+) T cells interact by adhesion complexes similar to immunological synapses. Tumor-cell killing was likely based on the recognition of allogeneic major histocompatibility complex class II (MHC-II) receptor, while CD4(+) T cells from MHC-II compatible donors did not develop any antitumor potential in case of HL cell line L428. However, gene expression profiling (GEP) of co-cultured HRS cells as well as tumor infiltration of matched CD4(+) T cells indicated cellular interactions. Moreover, matched CD4(+) T cells could be activated to kill CD30(+) HRS cells when redirected with a CD30-specific chimeric antigen receptor. Our work gives novel insights into the crosstalk between HRS and CD4(+) T cells, suggesting the latter as potent effector cells in the adoptive cell therapy of HL.
authors.affiliation: Dr. Senckenberg Institute of Pathology, Goethe-University of Frankfurt, Medical School , Frankfurt am Main, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Rengstl
authors.affiliation: Dr. Senckenberg Institute of Pathology, Goethe-University of Frankfurt, Medical School , Frankfurt am Main, Germany.
authors.forename: Frederike
authors.initials: F
authors.lastname: Schmid
authors.affiliation: Dr. Senckenberg Institute of Pathology, Goethe-University of Frankfurt, Medical School , Frankfurt am Main, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Weiser
authors.affiliation: Dr. Senckenberg Institute of Pathology, Goethe-University of Frankfurt, Medical School , Frankfurt am Main, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Döring
authors.affiliation: Dr. Senckenberg Institute of Pathology, Goethe-University of Frankfurt, Medical School , Frankfurt am Main, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Heinrich
authors.affiliation: Dr. Senckenberg Institute of Pathology, Goethe-University of Frankfurt, Medical School, Frankfurt am Main, Germany; Center for Molecular Medicine Cologne, University of Cologne, and Department I of Internal Medicine, University Hospital Cologne, Cologne, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Warner
authors.affiliation: Institute for Transfusion Medicine and Immunohematology, Red Cross Blood Donor Service , Baden-Württemberg-Hessen, Frankfurt, Germany.
authors.forename: Petra S A
authors.initials: PS
authors.lastname: Becker
authors.affiliation: Dr. Senckenberg Institute of Pathology, Goethe-University of Frankfurt, Medical School , Frankfurt am Main, Germany.
authors.forename: Robin
authors.initials: R
authors.lastname: Wistinghausen
authors.affiliation: Dr. Senckenberg Institute of Pathology, Goethe-University of Frankfurt, Medical School , Frankfurt am Main, Germany.
authors.forename: Sima
authors.initials: S
authors.lastname: Kameh-Var
authors.affiliation: Dr. Senckenberg Institute of Pathology, Goethe-University of Frankfurt, Medical School , Frankfurt am Main, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Werling
authors.affiliation: Dr. Senckenberg Institute of Pathology, Goethe-University of Frankfurt, Medical School , Frankfurt am Main, Germany.
authors.forename: Arne
authors.initials: A
authors.lastname: Billmeier
authors.affiliation: Institute for Transfusion Medicine and Immunohematology, Red Cross Blood Donor Service , Baden-Württemberg-Hessen, Frankfurt, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Seidl
authors.affiliation: Dr. Senckenberg Institute of Pathology, Goethe-University of Frankfurt, Medical School , Frankfurt am Main, Germany.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Hartmann
authors.affiliation: Center for Molecular Medicine Cologne, University of Cologne, and Department I of Internal Medicine, University Hospital Cologne , Cologne, Germany.
authors.forename: Hinrich
authors.initials: H
authors.lastname: Abken
authors.affiliation: Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Medical School , Essen, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Küppers
authors.affiliation: Dr. Senckenberg Institute of Pathology, Goethe-University of Frankfurt, Medical School , Frankfurt am Main, Germany.
authors.forename: Martin-Leo
authors.initials: ML
authors.lastname: Hansmann
authors.affiliation: Dr. Senckenberg Institute of Pathology, Goethe-University of Frankfurt, Medical School , Frankfurt am Main, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Newrzela
keywords: CD4+ T cells; Hodgkin and Reed-Sternberg (HRS) cells; Hodgkin lymphoma; MHC-II compatible donors; anti-tumor reaction; chimeric antigen receptor (CAR)