An obstructive role of NK cells on metastatic growth of clear‑cell sarcoma cells in a xenoplant murine model

Abstract

Clear cell sarcoma (CCS) affects the deep soft tissues in young adults and is known to have high rates of metastasis, including lymphatic metastasis. In our previous study an xenoplant model of CCS was established, which exhibited local tumor growth, lymphatic metastasis, and distant metastasis in SCID-Beige mice. In the current study, the role of NK cells during metastasis in the same xenoplant murine model was investigated. Injection of murine or human NK cells significantly suppressed the metastasis of HS-MM CCS cells in SCID-Beige mice. Notably, reverse transcription-quantitative PCR analysis demonstrated that injection of NK cells did not alter the mRNA expression levels of ERSR1-ATF1 , which is specifically transcribed in CCS, in the buffy coat of circulating blood cells of HS-MM-xenoplanted SCID-Beige mice. BALB/c nude mice xenoplanted with HS-MM cells exhibited local growth without evident metastasis, whereas inoculation with the anti-asialo-GM1 antibody, which has previously been found to abolish NK-cell activity, resulted in metastasis of HS-MM cells in BALB/c nude mice. The injection of the anti-CD96 antibody, which increases the cytotoxicity of NK cells, significantly suppressed the metastasis of HS-MM cells in SCID-Beige mice. These results indicated that NK cells impaired the metastatic tumor microenvironments in the present mice xenoplant model.

Inhibitory Receptors and Immune Checkpoints Regulating Natural Killer Cell Responses to Cancer

“…A significant body of work from the Smyth group performed in various mouse cancer models suggests that CD96 might limit NK cell-mediated protection against metastases and, therefore, blocking CD96 would enhance NK cell production of IFN-γ and cancer control [ 44 , 69 , 70 ]. While these data are in line with a study showing anti-tumor activity of anti-CD96 mAbs against a human clear cell carcinoma cell line xenotransplanted in SCID beige mice [ 71 ], they are opposed by a recent report indicating that CD96 crosslinking activates mouse and human CD8 + T cells [ 43 ]. This latest evidence would advocate against the use of CD96 blocking in cancer patients.…”

Prospects for NK Cell Therapy of Sarcoma

“…NK cells are known for their antimetastatic potential [ 85 , 86 , 87 , 88 ]. Indicators of NK cell function such as high expression of NK cell-activating receptors and high cytotoxic or IFN-γ secreting properties have been linked to decreased metastatic load in multiple cohorts of cancer patients with risk of metastatic disease, suggesting their clinically relevant protective role [ 87 ].…”