title: Reversal of tumor acidosis by systemic buffering reactivates NK cells to express IFN-γ and induces NK cell-dependent lymphoma control without other immunotherapies.
abstract: Like other immune cells, natural killer (NK) cells show impaired effector functions in the microenvironment of tumors, but little is known on the underlying mechanisms. Since lactate acidosis, a hallmark of malignant tissue, was shown to contribute to suppression of effective antitumor immune responses, we investigated the impact of tissue pH and lactate concentration on NK-cell functions in an aggressive model of endogenously arising B-cell lymphoma. The progressive loss of IFN-γ production by NK cells observed during development of this disease could be ascribed to decreased pH values and lactate accumulation in the microenvironment of growing tumors. Interestingly, IFN-γ expression by lymphoma-derived NK cells could be restored by transfer of these cells into a normal micromilieu. Likewise, systemic alkalization by oral delivery of bicarbonate to lymphoma-developing mice was capable of enhancing IFN-γ expression in NK cells and increasing the NK-cell numbers in the lymphoid organs where tumors were growing. By contrast, NK-cell cytotoxicity was dampened in vivo by tumor-dependent mechanisms that seemed to be different from lactate acidosis and could not be restored in a normal milieu. Most importantly, alkalization and the concomitant IFN-γ upregulation in NK cells were sufficient to significantly delay tumor growth without any other immunotherapy. This effect was strictly dependent on NK cells.
authors.affiliation: Institut für Molekulare Immunologie, Helmholtz-Zentrum München, Germany.
authors.forename: Johann
authors.initials: J
authors.lastname: Pötzl
authors.affiliation: Institut für Molekulare Immunologie, Helmholtz-Zentrum München, Germany.|AG Translationale Molekulare Immunologie, Helmholtz-Zentrum München, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Roser
authors.affiliation: Institut für Molekulare Immunologie, Helmholtz-Zentrum München, Germany.
authors.forename: Lorenz
authors.initials: L
authors.lastname: Bankel
authors.affiliation: Institut für Molekulare Immunologie, Helmholtz-Zentrum München, Germany.|AG Translationale Molekulare Immunologie, Helmholtz-Zentrum München, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Hömberg
authors.affiliation: Institut für Molekulare Immunologie, Helmholtz-Zentrum München, Germany.|AG Translationale Molekulare Immunologie, Helmholtz-Zentrum München, Germany.
authors.forename: Albert
authors.initials: A
authors.lastname: Geishauser
authors.affiliation: Institut für Molekulare Immunologie, Helmholtz-Zentrum München, Germany.
authors.forename: Christoph D
authors.initials: CD
authors.lastname: Brenner
authors.affiliation: Institut für Laboratoriumsmedizin, Ludwig-Maximilians-Universität München, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Weigand
authors.affiliation: Universitäts-Hautklinik, Eberhard-Karls-Universität, Tübingen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Röcken
authors.affiliation: Institut für Molekulare Immunologie, Helmholtz-Zentrum München, Germany.|AG Translationale Molekulare Immunologie, Helmholtz-Zentrum München, Germany.
authors.forename: Ralph
authors.identifier: 0000-0003-0141-4937
authors.initials: R
authors.lastname: Mocikat
mesh_terms: D000138:Acidosis / Q000235:genetics* / Q000276:immunology; D000818:Animals; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007111:Immunity, Cellular / Q000235:genetics; D007167:Immunotherapy; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D019344:Lactic Acid / Q000378:metabolism*; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D059016:Tumor Microenvironment / Q000235:genetics
chemical_list: D019344:Lactic Acid; D007371:Interferon-gamma
keywords: NK-cell activation; bicarbonate; endogenous B-cell lymphoma; tumor escape; λ-myc mouse