Recruitment of Natural Killer Cells in Advanced Stages of Endogenously Arising B-cell Lymphoma

Abstract

During inflammation and in transplantable tumor models, natural killer (NK) cells are recruited to pathologic tissues and activated to produce proinflammatory cytokines favoring adaptive immune responses of the T-helper type 1 (Th1) type. Interferon (IFN)-γ is needed to induce chemokines that attract NK cells in transplanted tumors. Nothing, however, is known on NK-cell migration in spontaneous tumors. As effective recruitment is a prerequisite for therapeutic NK-cell transfer, we investigated the cytokine milieu and the mechanisms that are instrumental for NK-cell accumulation in an endogenous tumor model. We make use of λ-myc transgenic mice that harbor the c-myc oncogene and develop spontaneous B-cell lymphoma. In contrast to lymphomas induced by tumor cell injection, virtually no IFN-γ produced by NK or by other cells was present in the tumor environment, particularly in advanced stages. Dendritic cells showed an impaired expression of interleukin-12, which is suggestive of deficient Th1 priming. The IFN-γ-dependent chemokines CXCL9 and CXCL10 were pivotal for NK-cell migration in the endogenous lymphoma model. Although IFN-γ was absent in late tumor stages, there was still expression of CXCL9 and CXCL10 with an ongoing influx of NK cells. The results demonstrate that transplantable tumor models do not reflect the situation as found in endogenously arising neoplasia, because in the latter, effective Th1 and cytotoxic T-lymphocyte responses are presumably not induced because of impaired IFN-γ production. The data also suggest that CXCL9 and CXCL10 production and NK-cell migration become independent of IFN-γ during tumor progression, and therefore support approaches of adoptive NK-cell transfer that hold promise for treatment of cancer.