krn-7000 and Colonic-Neoplasms

Non-conventional T cells, such as γδ T and invariant natural killer T (iNKT) cells, are emerging players in fighting cancer. Alpha-galactosylceramide (α-GalCer) is used as an exogenous ligand to activate iNKT cells. Human cells don't have a direct pathway producing α-GalCer, which, however, can be produced by bacteria. We searched the literature for bacteria strains that are able to produce α-GalCer and used available sequencing data to analyze their presence in human tumor tissues and their association with survival. The modulatory effect of antibiotics on the concentration of α-GalCer was analyzed in mice. The human gut bacteria

Topics: Adenocarcinoma; Animals; Bacteroides; Colonic Neoplasms; Galactosylceramides; Immunotherapy; Mice; Mice, Inbred C57BL; Natural Killer T-Cells; Prevotella

Murine and human invariant natural killer T (iNKT) lymphocytes are activated by α-galactosylceramide (α-GalCer) presented on CD1d. α-GalCer was first described as a lipid that had strong anti-metastatic effects in a mouse melanoma model, and it has subsequently been shown to induce efficient iNKT cell dependent tumor immunity in several tumor models. We have shown that α-GalCer treatment leads to a weak reduction of polyp burden in the autochthonous

Topics: Adenomatous Polyposis Coli Protein; Animals; Antibodies, Blocking; Colonic Neoplasms; Female; Galactosylceramides; Humans; Intestinal Mucosa; Intestinal Polyps; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Natural Killer T-Cells; Neoplasms, Experimental; Programmed Cell Death 1 Receptor; T-Lymphocytes, Regulatory; Th1 Cells

Dendritic cells (DCs) and invariant natural killer T (iNKT) cells play important roles in linking innate immunity and adaptive immunity. Mature DCs activated by Toll-like receptor (TLR) agonists directly activate iNKT cells and the iNKT ligand α-galactosylceramide (α-Galcer) can induce DC maturation, resulting in enhanced protective immune responses. In the present study, we aimed to boost anti-tumour immunity in a murine colon cancer model by synergizing DCs and iNKT cells using α-Galcer-loaded tumour cells (tumour-Gal) and the TLR9 agonist cytosine-phosphorothioate-guanine (CpG1826). The vaccine strategy was sufficient to inhibit growth of established tumours and prolonged survival of tumour-bearing mice. Importantly, the immunization induced an adaptive memory immune response as the survivors from primary tumour inoculations were resistant to a tumour re-challenge. Furthermore, injection of tumour-Gal with CpG1826 resulted in iNKT cell activation and DC maturation as defined by interferon (IFN)-γ secretion by iNKT, natural killer (NK) cells and interleukin (IL)-12 by DCs. Immunohistochemistry analysis revealed that cluster of differentiation (CD)4(+) T-cells and CD8(+) T-cells played important roles in anti-tumour immunity. Additionally, the vaccine redirected Th2 (T-helper cell type 2) responses toward Th1 (T-helper cell type 1) responses with increases in IL-2, IFN-γ expression and decreases in IL-4 and IL-5 expression after immunization with tumour-Gal with CpG1826. Taken together, our results demonstrated a novel vaccination by synergizing tumour-Gal and CpG1826 against murine colon cancer, which can be further developed as tumour-specific immunotherapy against human cancer.

Topics: Animals; Antineoplastic Agents; Cancer Vaccines; Coculture Techniques; Colonic Neoplasms; Disease Models, Animal; Female; Galactosylceramides; Mice; Mice, Inbred C57BL; Toll-Like Receptor 9; Treatment Outcome; Tumor Cells, Cultured

We aimed to investigate whether allogeneic dendritic cells pulsed with alpha-galactosylceramide (DCG) treatment induces activation of Natural Killer T (NKT) cells.. C57BL/6 and BALB/c mice were injected with syngeneic and allogeneic DCG. We then examined NK and NKT cell activity in the lung and spleen and antitumor effect in various lung tumor metastatic models.. While splenic NKT activity was suppressed after allogeneic DCG treatment, allogeneic DCG treatment induced similar antitumor effect as well as lung NKT and NK cell activity compared to syngeneic DCG treatment. Furthermore, allogeneic DCG treatment prolonged survival in B16F10, LLC, Pan02, MethA, and CT26 tumor models in two strains of mice.. This allogeneic DCG treatment could be substituted for syngeneic DCG treatment. The results obtained in the present study suggest that allogeneic DCG treatment may provide a new approach in cancer immunotherapy with NKT cells.

Topics: Animals; Colonic Neoplasms; Female; Galactosylceramides; Interferon-gamma; Lung Neoplasms; Lymphocyte Activation; Mammary Neoplasms, Experimental; Melanoma, Experimental; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Natural Killer T-Cells

α-Galactosylceramide (α-GalCer) has been reported to be therapeutic against metastatic liver tumors in mice. However, little is known regarding the efficacy of combined chemo-immunotherapy using α-GalCer and anticancer drugs. In this study, we evaluated the antitumor effect of the combination therapy of α-GalCer and 5-fluorouracil (5-FU) against liver tumors of MC38 colon cancer cells. The liver weights of tumor-bearing mice treated with the combination were significantly lower than those of nontreated mice and of mice treated with 5-FU or α-GalCer alone. No toxic effects on the liver and renal functions were observed in any of the treatment groups. α-GalCer treatment induced significant activation of liver NK cells in vivo, but 5-FU treatment did not. 5-FU treatment resulted in a significant upregulation of NKG2D activating molecules (Rae-1 and H60) and DNAM-1 ligands (CD112 and CD155) on MC38 cells, but α-GalCer did not. The cytolytic activity of α-GalCer-activated liver mononuclear cells against 5-FU-treated MC38 cells was significantly higher than that against nontreated cells. The increase of the cytolytic activity induced by 5-FU partially depended on NKG2D-Rae-1 or H60 signals. Depletion of NK cells significantly inhibited the antitumor efficacy of 5-FU against MC38 liver tumors, which suggested that the antitumor effect of 5-FU partially depended on the cytolytic activity of NK cells. These results demonstrated that the combination therapy of α-GalCer and 5-FU produced synergistic antitumor effects against liver tumors by increasing the expression of NK activating molecules on cancer cells. This study suggests a promising new chemo-immunotherapy against metastatic liver cancer.

Topics: Animals; Cell Line, Tumor; Colonic Neoplasms; Cytotoxicity, Immunologic; Drug Synergism; Female; Fluorouracil; Galactosylceramides; Killer Cells, Natural; Liver Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL

Whole body hyperthermia (WBH) has been used clinically as an adjunct to radio- and chemotherapy in patients with various cancers. Recently, it has been reported that an activation of the immune system has recently been reported as a possible contributor to the therapeutic effects of WBH. Conversely, the glycolipid alpha-galactosylceramide (alpha-GalCer) is recognized by natural killer (NK) T cells together with the monomorphic MHC-like antigen, CD1d, in mice and humans. This study investigated the antitumor effects of WBH combined with alpha-GalCer in a mouse subcutaneous tumor model of colon cancer.. Colon26 cells were inoculated subcutaneously into male BALB/c mice to establish subcutaneous tumor. Colon26-bearing mice were treated with WBH using far infrared rays three times/week. Rectal temperature was maintained for 60 min at 41 degrees C. In some experimental groups, alpha-GalCer was intraperitoneally injected before WBH. We investigated the therapeutic effects of WBH, alpha-GalCer and combined therapy.. (1) Compared with controls, WBH alone resulted in significant inhibition of tumor growth. (2) No inhibitory effect on tumor growth was seen with alpha-GalCer. (3) The combination of WBH and alpha-GalCer showed significant inhibition of tumor growth and prolongation of survival. (4) Serum IFN-gamma increased after 3 h and returned to basal levels by 24 h after alpha-GalCer administration. (5) CTL activity was enhanced following combination therapy with WBH and alpha-GalCer.. WBH showed antitumor effects in a mouse subcutaneous tumor model of colon cancer. Addition of alpha-GalCer increased the efficacy of WBH, probably via enhancement of immune response.

Topics: Animals; Cell Line, Tumor; Colonic Neoplasms; Combined Modality Therapy; Galactosylceramides; Humans; Hyperthermia, Induced; Interferon-gamma; Male; Mice; Mice, Inbred BALB C; T-Lymphocytes, Cytotoxic

Although resting B cells are known for being poorly immunogenic and for inducing T-cell tolerance, we have here attempted to test whether their immunogenicity could be enhanced by CD1d-restricted invariant T cells (iNKT) to a point where they could be used in cellular vaccines. We found that the addition of the iNKT ligand alpha-galactosylceramide (alphaGalCer) to peptide-loaded B cells overcame peptide-specific T-cell unresponsiveness and allowed for the generation of peptide-specific memory CTL immunity. This CTL was induced independently of CD4 T and natural killer cells but required iNKT and CD8 T cells. B cells directly primed CTL, and the alphaGalCer and the peptide must be presented on the same cell. Importantly, our B-cell-based vaccine is comparable in efficiency with dendritic cell-based vaccines, inducing similar CTL responses as well as providing an effective regimen for preventing and suppressing s.c. and metastatic tumors. Therefore, with the help of iNKT, peptide-pulsed B cells can establish long-lasting antitumor immunity and so show promise as the basis for an alternative cell-based vaccine.

Topics: Animals; Antigens, CD1; Antigens, CD1d; B-Lymphocytes; Cancer Vaccines; Colonic Neoplasms; Female; Galactosylceramides; Immunologic Memory; Immunotherapy, Adoptive; Melanoma, Experimental; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; T-Lymphocytes, Cytotoxic

The novel immunomodulator (2S,3S,4R)-I-O-(alpha-D-galactopyranosyl)-2- (N-hexacosanoylamino)-1,3,4-octadecanetriol (KRN7000) in combination with high-dose (20 and 30 Gy) local x-ray irradiation or low-dose (3 Gy) fractionated whole-body irradiation showed significantly stronger antitumor activities against Meth A-and Colon26-bearing mice than treatments by radiation or KRN7000 alone, and 60% of mice in combination treatment groups were cured. Furthermore, the results of tests rechallenging the cured mice with Meth A and Colon26 cells strongly suggested that tumor-specific immunity was induced by the combination treatment. The suggestion was supported by the result that the systemic administration of KRN7000 could produce large amounts of interleukin-2 and interferon-gamma, which contribute to induction of tumor-specific cytotoxic lymphocytes not only in normal mice but also in whole-body irradiated mice. Furthermore, it was also suggested that KRN7000 contributes to protecting antitumor effector cells, such as natural killer cells, from impairments caused by radiation. Taking together the results and the knowledge that tumor-specific cytotoxic lymphocytes play a critical role in prevention of tumor recurrence and distant metastasis, it is strongly suggested that combined therapy with KRN7000 and radiation could be quite useful for cancer treatment.

Topics: Adjuvants, Immunologic; Animals; Carcinoma; Colonic Neoplasms; Combined Modality Therapy; Drug Screening Assays, Antitumor; Female; Galactosylceramides; Killer Cells, Natural; Mice; Neoplasm Transplantation; Sarcoma, Experimental; Whole-Body Irradiation; X-Ray Therapy