Description
Significant racial disparity exists in colorectal cancer (CRC). African Americans (AA) have higher incidence rates, mortality rates, and poorer prognosis compared to Caucasian Americans (CA). In both human and animal studies, anti-tumor immunity, especially cytotoxic T lymphocyte (CTL) activity in tumor environments, has proved to strongly inhibit tumor development and metastasis, and improve clinical outcome and survival in CRC. In this study, previous immunohistochemistry staining for granzyme B in 177 microsatellite stable colon tumors samples (83AA vs. 94CA) was reanalyzed to evaluate CTL activity in tumor environment. In two different histological locations, intratumoral (p=0.02) and invasive border (p=0.0006), CA patients have significantly higher numbers of granzyme B expressing cells infiltrating their tumors compared to AA patients. This result reveals that anti-tumor cytotoxicity may contribute to the racial disparities in CRC. Also, a potential therapy for CRC has been tested in a mouse model (colon-specific Apc gene knockout) in this study. Engineered bacterial minicells, VAX-IP, are noninfectious, nano-sized bacteria that can directly target two tumor cell specific surface integrins (α5β1 or α3β1), and deliver a bacterial cytolysin protein, perfringolysin O, to rapidly destroy malignant cells. Our study shows that VAX-IP treatment (1 dose/ week, 6 doses total) during lesion development stage (age 14–19th weeks) or lesions absent/initial stage (age 8–13th weeks) can both significantly decrease tumor burden (p=0.015 and 0.046, separately) in CRC mice harvested at 26 weeks of age. Studies have shown that inflammatory mediators infiltrating in tumor environments significantly contribute to tumor progression in CRC. To explore the mechanism and reveal the influence of VAX-IP in tumor inflammation environment, immunohistochemistry for CD11b, a biomarker for inflammatory, myeloid-lineage cells, was applied in tumors and/or normal adjacent tissue, which showed decreased expression in 14–19th VAX-IP-treated mice versus controls (p=0.003) but not parental mice (p=0.90). Besides, Chloracetate Esterase (CAE) staining of inflammatory granulocytes and mast cells also showed less CAE + infiltrating cells in VAX-IP treated mice, especially in colon crypts areas (p=0.02). These results strongly suggest that VAX-IP reduces inflammatory infiltration of myeloid cells into the colonic environment, contributing to the reduced tumor load in this mouse model.
