krn-7000 and Colorectal-Neoplasms

Patients with colorectal cancer frequently develop liver metastases after, and perhaps as a consequence of, lifesaving surgical resection of the primary tumor. This creates a potential opportunity for prophylactic metastatic treatment with novel immunostimulatory molecules. Here, we used state-of-the-art intravital imaging of an experimental liver metastasis model to visualize the early behavior and function of invariant natural killer T (iNKT) cells stimulated with α-galactosylceramide (α-GalCer). Intravenous α-GalCer prior to tumor cell seeding in the liver significantly inhibited tumor growth. However, some seeding tumor cells survived. A multiple dosing regimen reduced tumor burden and prolonged the life of mice, whereas tumors returned within 5 days after a single dose of α-GalCer. With multiple doses of α-GalCer, iNKT cells increased in number and granularity (as did NK cells). As a result, the total number of contacts and time in contact with tumors increased substantially. In the absence of iNKT cells, the beneficial effect of α-GalCer was lost. Robust cytokine production dissipated over time. Repeated therapy, even after cytokine dissipation, led to reduced tumor burden and prolonged survival. Serial transplantation of tumors exposed to α-GalCer-activated iNKT cells did not induce greater resistance, suggesting no obvious epigenetic or genetic immunoediting in tumors exposed to activated iNKT cells. Very few tumor cells expressed CD1d in this model, and as such, adding monomers of CD1d-α-GalCer further reduced tumor growth. The data suggest early and repeated stimulation of iNKT cells with α-GalCer could have direct therapeutic benefit for patients with colorectal cancer who develop metastatic liver disease.

Topics: Animals; Antigens, CD1d; Cell Line, Tumor; Colorectal Neoplasms; Disease Models, Animal; Galactosylceramides; Liver Neoplasms; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Natural Killer T-Cells; Neoplasm Metastasis

Invariant natural killer T (iNKT) cells are considered innate-like lymphocytes, and regulate the immunity against inflammation and tumorigenesis. However, the impact of iNKT cells in inflammation-associated tumorigenesis remains unclear. In this study, we examined the physiological role of iNKT cells in a mouse colitis-associated colorectal cancer model. C57BL/6 (B6) and Jα18 NKT cell-deficient KO (KO) mice were used. Colitis-associated colorectal cancer was induced by azoxymethane (AOM) and dextran sodium sulfate (DSS). The resulting inflammation and tumours were examined. The surface markers of mononuclear cells from the liver and the colon were assessed by FACS. The levels of IL-13 from the colon were measured by ELISA. α-galactosylceramide (GC), or its close analog OCH, was administered intraperitoneally on the first day of each cycle of DSS-administration. In the AOM/DSS model, hepatic iNKT cells were significantly decreased. In KO mice there were significantly greater numbers of colon tumours and more severe inflammation than in B6 mice. FACS analysis revealed that the population of NK1.1 (+) T cells (non-invariant NKT cells) in the colon was increased when compared to B6 mice. The secretion of IL-13 was increased in the colon of KO mice after AOM/DSS. The number of colon tumours was significantly decreased in the GC-treated group compared to the control group. GC-treatment significantly inhibited IL-13 secretion from the colonic mononuclear cells and the number of colonic NK1.1 (+) T cells was significantly decreased. These results suggest that iNKT cells may play a critical role in the prevention of tumour progression and inflammation in the AOM/DSS model.

Topics: Animals; Colitis; Colorectal Neoplasms; Disease Models, Animal; Flow Cytometry; Galactosylceramides; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Natural Killer T-Cells; Specific Pathogen-Free Organisms

Colorectal liver metastasis is clinically a major problem. We examined the antitumor activity of KRN7000, an alpha-galactosylceramide, on mice with liver metastases of adenocarcinoma Colon26 cells. KRN7000 treatment, beginning 1 day after tumor inoculation (day 1), significantly inhibited tumor growth in the liver, and its potency was equal to that of interleukin 12. KRN7000 treatment from day 3 caused regression of established Colon26 nodules. KRN7000 administration resulted in a high percentage of cured mice that acquired tumor-specific immunity. In addition, it appeared that highly activated, liver-associated natural killer cells made the major contribution to the killing of Colon26 cells in the liver. These results suggest that KRN7000 may be useful for the treatment of colorectal liver metastasis.

Topics: Adenocarcinoma; Adjuvants, Immunologic; Animals; Antineoplastic Agents; Colorectal Neoplasms; Cytotoxicity, Immunologic; Dose-Response Relationship, Drug; Female; Galactosylceramides; Interleukin-12; Killer Cells, Natural; Leukocytes, Mononuclear; Liver; Liver Neoplasms; Mice; Mice, Inbred BALB C; Neoplasms, Experimental