Mechanism of Genetically-Regulated Response to Bacillus- Calmette Guérin Immunotherapy for Bladder Cancer

In this study, we investigated host response to Bacillus-Calmette Guérin (BCG) immunotherapy using the murine MM45T bladder tumor cell line. BALB/c (Bcgs allele) and BALB/c.CD2 (CD2) (Bcgr allele) mice were seeded subcutaneously with MM45T cells. Treatment began on day 7 with intra-tumor injections of BCG. Significant decreases in tumor growth in BALB/c (p < 0.05) but not in the CD2 (p = NS) mice were observed 6, 10 and 14 days following treatment. Investigation of the mechanism(s) underlining the difference in the response between the two strains of mice revealed key points, namely: (i) Intraperitoneal injection of BCG led to a significant increase (p < 0.05) in the number of cells recovered 14 days later by peritoneal lavage (in million cells: 5.1 ± 0.7 vs 9.5 ± 0.3 in BALB/c and 5.3 ± 0.4 vs 7.0 ± 0.4 in CD2, PBS vs BCG). (ii) Compositional analysis of the lavages following BCG injection indicated a significant increase in the lymphocyte/macrophage ratio in BALB/c mice as compared to CD2 mice (p < 0.05). (iii) Activated peritoneal macrophage production of nitric oxide (NO) was significantly lower (p < 0.05) in BALB/c than in CD2 (26.8 ± 1.6 vs 38.3 ± 0.7 uM of nitrite respectively) when challenged with lipopolysaccharide. (iv) No difference in the in vitro cytotoxicity against MM45T cells was observed between BALB/c and CD2 macrophages. Our results suggest that differences in the composition of monocytes infiltrating the site of BCG treatment and in the release of substances such as NO by macrophages may be key determinants of the response to BCG immunotherapy for bladder cancer.