title: Efficacy of CAR T-cell therapy in large tumors relies upon stromal targeting by IFNγ.
abstract: Adoptive T-cell therapy using chimeric antigen receptor-modified T cells (CAR-T therapy) has shown dramatic efficacy in patients with circulating lymphoma. However, eradication of solid tumors with CAR-T therapy has not been reported yet to be efficacious. In solid tumors, stroma destruction, due to MHC-restricted cross-presentation of tumor antigens to T cells, may be essential. However, CAR-Ts recognize antigens in an MHC-independent manner on cancer cells but not stroma cells. In this report, we show how CAR-Ts can be engineered to eradicate large established tumors with provision of a suitable CD28 costimulatory signal. In an HER2-dependent tumor model, tumor rejection by HER2-specific CAR-Ts was associated with sustained influx and proliferation of the adoptively transferred T cells. Interestingly, tumor rejection did not involve natural killer cells but was associated instead with a marked increase in the level of M1 macrophages and a requirement for IFNγ receptor expression on tumor stroma cells. Our results argue that CAR-T therapy is capable of eradicating solid tumors through a combination of antigen-independent stroma destruction and antigen-specific tumor cell targeting.
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Ana
authors.initials: A
authors.lastname: Textor
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Joanna J
authors.initials: JJ
authors.lastname: Listopad
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Lara Le
authors.initials: LL
authors.lastname: Wührmann
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Perez
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Kruschinski
authors.affiliation: Department I of Internal Medicine, Tumor Genetics, and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Chmielewski
authors.affiliation: Department I of Internal Medicine, Tumor Genetics, and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
authors.forename: Hinrich
authors.initials: H
authors.lastname: Abken
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Berlin, Germany. Institute of Immunology, Charite Campus Buch, Berlin, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Blankenstein
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Berlin, Germany. jehad.charo@roche.com.
authors.forename: Jehad
authors.initials: J
authors.lastname: Charo
mesh_terms: D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D064987:Cell- and Tissue-Based Therapy / Q000379:methods; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D007371:Interferon-gamma / Q000276:immunology* / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D017471:Receptors, Interferon / Q000276:immunology / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000378:metabolism; D017154:Stromal Cells / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D018106:CD28 Antigens; D007371:Interferon-gamma; D018719:Erb-b2 Receptor Tyrosine Kinases; D011948:Receptors, Antigen, T-Cell; D017471:Receptors, Interferon; D011993:Recombinant Fusion Proteins; C508053:ERBB2 protein, human