Abstract 1541: NK cells are indispensable for suppression of tumor growth and metastasis in transgenic mice overexpressing chemokine CXCL14/BRAK

Abstract

Abstract [PURPOSE] We reported previously that the forced expression of the chemokine CXCL14/BRAK (BRAK) in head and neck squamous cell carcinoma (HNSCC) cells decreased the rate of tumor formation and size of tumor cell transplants compared with those of mock vector-treated cells in athymic nude mice or in severe combined immunodeficiency (SCID) mice, even though the growth rates of these cells were the same under in vitro culture conditions. The aim of this study was to determine whether BRAK transgenic mice (Tg) would show resistance to tumor cell transplant and tumor metastasis or not, and if so, to find the mechanism of tumor suppression. [EXPERIMENTAL PROCEDURES] Lewis lung carcinoma (LLC) cells or B16 melanoma cells were injected subcutaneously into dorso-lateral region of Tg or wild type (Wt) C57BL/6J mice. Tumor cells were also injected intravenously via a tail vein into Wt, SCID mice or NK cell-deficient NOG mice to investigate colonization to the lungs. Tg or Wt mice were also pre-injected with NK cell function inhibitory anti-NK 1.1 antibody or anti-asialo GM1 antibody to see the role of NK cells in BRAK-dependent tumor suppression in vivo. Melanoma cells that had been engineered to express the BRAK gene under the control of doxycycline (B16-luc-2-LMT3-Tet/OnBRAK) were also used. [RESULTS] Sizes of LLC or B16 melanoma cell tumors in the Tg mice were significantly smaller than those in the control Wt mice, indicating that BRAK, first found as a suppressor of tumor growth of head and neck squamous cell carcinomas, also suppressed the growth of carcinomas of other tissue origins. This suppression was attenuated by the injection of anti-asialo-GM1 antibody. Colonization of LLC cells or B16 melanoma cells to the lungs was also suppressed in the Tg mice, and this suppression was attenuated by the treatment with anti-asialo-GM1 antibody or anti-NK 1.1 antibody. When Wt mice were fed doxycycline-containing sucrose solution after the injection of B16-luc-2-LMT3-Tet/OnBRAK cells, the number of metastatic nodules in the lungs was significantly lower than that for the mice fed control sucrose solution. In the case of SCID mice, the number of metastatic nodules was 4 times higher that for the Wt, but still the number was significantly lower than that for the BRAK-expressing melanoma cells. On the other hand, when the B16-luc-2-LMT3-Tet/OnBRAK cells were injected into NK-cell-deficient NOG mice, the number of metastatic nodules was ten times higher than that in the Wt mice; and also no difference was observed between BRAK-expressing and non-expressing melanoma cells, indicating NK cell activity to be indispensable for suppression of tumor-cell metastasis to the lung. [CONCLUSION] High expression of the BRAK gene either in host cells, or tumor cells resulted in suppression of growth and metastasis of tumor cells, and NK cells were indispensable for either suppression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1541. doi:1538-7445.AM2012-1541