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Pötzl, Johann; Roser, David; Bankel, Lorenz; Hömberg, Nadine; Geishauser, Albert; Brenner, Christoph D.; Weigand, Michael; Röcken, Martin; Mocikat, Ralph (2017): Reversal of tumor acidosis by systemic buffering reactivates NK cells to express IFN-gamma and induces NK cell-dependent lymphoma control without other immunotherapies. In: International Journal of Cancer, Vol. 140, No. 9: pp. 2125-2133
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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-gamma 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-gamma 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-gamma 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-gamma upregulation in NK cells were sufficient to significantly delay tumor growth without any other immunotherapy. This effect was strictly dependent on NK cells.