Tumor-associated NK cells facilitate tumor growth via NKp46 in immunocompetent murine hepatocellular carcinoma

Abstract

Natural killer(NK) cells comprise one subset of the innate lymphoid cells family. Despite reported anti-tumor activity of NK cells, their tangible contribution to tumor control remains controversial. This is due to the incomplete understanding of NK alterations within tumor microenvironment(TME). Here we showed, using murine hepatocellular carcinoma(HCC) model, that early NK cells deletion markedly attenuated tumor growth in a CD8⁺T cells dependent manner. This effect was accompanied by an enhanced CD8⁺T cells effector function in tumor rather than circulating blood. Then, we demonstrated that abundant NKp46⁺ NK subset, but not NKp46^- NK, were recruited towards tumor microenvironment during tumor progression. Frequency of intratumor NKP46⁺ NK cells were inversely related to CD8⁺T cells activation, and positively correlated with tumor growth. Intratumor NKp46⁺ NK cells exhibited dysfunction and increased expression of inhibitory receptors, when compared with NKp46^- NK cells. Blockade of NK cells-associated NKp46 effectively attenuated HCC growth. Infusion of tumor-derived NKp46⁺ NK cells markedly enhanced HCC growth in vivo, in contrast to tumor cells inoculation alone. The further mechanistic investigations unveiled that NK cells boosted tumor growth by NKp46-mediated impairment of CD8⁺T cells effector function. Overall, this work supported a previously unappreciated regulatory property of tumor-associated NK cells in HCC, and NKp46 as a potential target against HCC in clinical setting.

Keywords: CD8(+)T cells; Hepatocellular carcinoma; NK cells; NKp46; Tumor microenvironment.