T cell immunity induced by a bivalent Salmonella-based CEACAM6 and 4-1BBL vaccines in a rat colorectal cancer model.

The present study investigated the anti-tumor mechanisms of recombinant non-specific cross-reacting antigen (CEACAM6) and 4-1BB ligand (4-1BBL) Salmonella-based vaccines, and the effect that these vaccinations have on memory T cells and T helper (Th) cell polarization. Colon tumors were induced in rats via 1,2-dimethylhydrazine (DMH) injections. Rats were then treated with injections of attenuated Salmonella typhimurium carrying pIRES-CEACAM6, pIRES-4-1BBL or pIRES-CEACAM6-4-1BBL. In total, 4 vaccine injections, one every other week, were administered during the 8 weeks subsequent to the DMH injection. Rats were sacrificed 18 weeks subsequent to the DMH injections, and the colons and spleens were collected for further analysis. Cluster of differentiation (CD) 45RO, interleukin (IL)-4 and IL-17 expression was analyzed in colon tumor tissues, and the expression of interferon (IFN)-γ, CD3+, CD4+, CD8+, CD56+, forkhead/winged-helix transcription factor box P3 (FOXP3+), IL-4 and IL-17 were analyzed in splenic tissues. Compared with the pIRES/SL3261 group, the pIRES-CEACAM6-4-1BBL/SL3261 treatment group had a significantly higher number of CD45RO+ expressing tumor infiltrating lymphocytes and lower expression levels of IL-4 and IL-17. Splenic tissues from the same treatment group exhibited significantly increased expression of IFN-γ, CD3+ and CD8+ and reduced expression levels of Foxp3, IL-4 and IL-7. CD56+ T cell expression was increased in all groups except for the group that received no vaccine. The present study concluded that the combined CEACAM6 and 4-1BBL-attenuated recombinant Salmonella vaccine was able to inhibit the growth of DMH-induced colorectal tumors. This was mediated by generating an anti-tumor immune response, increasing the number of of CD45RO+ memory T cells, decreasing the number of FOXP3+ cells and promoting Th1 polarization.

Recombinant Salmonella-based CEACAM6 and 4-1BBL vaccine enhances T-cell immunity and inhibits the development of colorectal cancer in rats: In vivo effects of vaccine containing 4-1BBL and CEACAM6.

The present study aimed to determine the effect of recombinant Salmonella (SL3261)-based CEACAM6 and 4-1BB ligand (4-1BBL) vaccine on the development of colorectal cancer in rats and the potential immune mechanisms involved. Attenuated Salmonella typhimurium (vaccine strain)­carrying plasmids pIRES-CEACAM6, pIRES­4­1BBL and pIRES-CEACAM6-4-1BBL were constructed. The rats were administered subcutaneous injections of 1,2-dimethyl-hydrazine (DMH) once a week for 18 weeks. Eight weeks after the first injection, the rats were divided into the pIRES/SL3261, pIRES-4-1BBL/SL3261, pIRES-CEACAM6/SL3261 and pIRES-CEACAM6-4-1BBL/SL3261 groups, and fed with corresponding vaccine strains. The rats were then sacrificed, the number of colon tumors were recorded, and the Dukes' stage were evaluated. CD3, CD4, CD8, CD56, FOXP3 and CEACAM6 expression in tumor tissues was determined by immunohistochemical staining. Compared with the expression levels in the pIRES/SL3261 group, similar levels of CD3+, CD8+ and CD56+ expression were identified for the pIRES-CEACAM6/SL3261 group of rats. Additionally, a comparable number of tumors was detected in the pIRES-4-1BBL/SL3261 and pIRES-CEACAM6/SL3261 groups. By contrast, a significantly fewer number of tumors, albeit with a higher density of CD3+CD8+, CD56+ and a lower density of Foxp3+ tumor-infiltrating lymphocyte (TIL) cells was detected in the pIRES-CEACAM6-4-1BBL/SL3261 group of rats. The results indicated that vaccination with recombinant attenuated Salmonella harboring the CEACAM6 and 4-1BBL gene efficiently increased the number of CD3+CD8+ TIL and NK cells, decreased the number of FOXP3 cells and inhibited the development of DMH-induced colorectal cancer in rats.

Changes in serum IGF-1 level and tumor VEGF expression in mice with colorectal cancer under hyperglycemic conditions.

The present study aimed to observe the growth of transplanted tumors in mice with colorectal cancer (CRC) under hyperglycemic conditions and to detect the expression of vascular endothelial growth factor (VEGF) in these tumors. The study also aimed to observe the changes in serum insulin-like growth factor-1 (IGF-1) levels and to determine whether type 2 diabetes mellitus (T2DM) was a risk factor for the progression and development of CRC. A mouse model of a transplanted colorectal tumor with T2DM was established to observe the changes in volume and size of the transplanted tumor. Mice were sacrificed at the end of the 5th week to determine the serum IGF-1 level and VEGF expression in the tumor tissues. The tumor volume (1628.5 ± 882 mm3) in the CRC-DM group was larger than that in the CRC group (1950.2 ± 726 mm3; P<0.05). The serum IGF-1 level (105.33 ± 32.32 ng/ml) was higher than that in the normal (69.83 ± 25.57 ng/ml) and CRC groups (70.17 ± 25.27 ng/ml; P<0.05). The VEGF expression in the tumor tissues of the CRC-DM group(70.0 ± 11.5%) was higher than that in the CRC group (42.9 ± 7.5%; P<0.05). T2DM may be one of the causes for the promotion of CRC growth and its mechanism may be correlated with the increased IGF-1 action observed in the blood that induces VEGF gene transcription, upregulates VEGF expression, causes tumor angiogenesis and thus leads to the occurrence and metastasis of tumors.