The efficacy of antitumoral responses can be increased using combinatorial vaccine strategies. We recently showed that vaccination could be optimized by local administration of diverse molecular or bacterial agents to target and augment antitumoral CD8 T cells in the genital mucosa (GM) and increase regression of cervical cancer in an animal model. Non muscle-invasive bladder cancer is another disease that is easily amenable to local therapies. In contrast to data obtained in the GM, in this study we show that intravesical (IVES) instillation of synthetic toll-like receptor (TLR) agonists only modestly induced recruitment of CD8 T cells to the bladder. However, IVES administration of Ty21a, a live bacterial vaccine against typhoid fever, was much more effective and increased the number of total and vaccine-specific CD8 T cells in the bladder approximately 10 fold. Comparison of chemokines induced in the bladder by either CpG (a TLR-9 agonist) or Ty21a highlighted the preferential increase in complement component 5a, CXCL5, CXCL2, CCL8, and CCL5 by Ty21a, suggesting their involvement in the attraction of T cells to the bladder. IVES treatment with Ty21a after vaccination also significantly increased tumor regression compared to vaccination alone, resulting in 90% survival in an orthotopic murine model of bladder cancer expressing a prototype tumor antigen. Our data demonstrate that combining vaccination with local immunostimulation may be an effective treatment strategy for different types of cancer and also highlight the great potential of the Ty21a vaccine, which is routinely used worldwide, in such combinatorial therapies.
Keywords: BCG, Bacillus Calmette Guerin; BMDC, bone marrow-derived dendritic cell; C5a, complement component 5a; ESL, E-selectin ligands; GM, genital mucosa; IVAG, intravaginal; IVES, intravesical; NMIBC, non-muscle invasive bladder cancer; PBS, phosphate buffered saline; PE, phycoerythrin; PIC, poly (I:C); SEM, standard error of the mean; Salmonella Ty21a; TLR, toll-like receptor; TUR, transurethral resection; bacterial immunostimulant; bladder cancer; combinatorial therapy; s.c., subcutaneously; therapeutic vaccination.