Tumor-induced immune suppression of therapeutic cancer vaccines

Therapeutic cancer vaccines offer an attractive strategy for treating cancer. Not only can the immune system specifically target tumor cells, but it also provides long-term memory needed to prevent recurrent disease. Despite the therapeutic appeal of cancer vaccines, they have not been effective clinically. Thus, we set out to determine the mechanisms by which the presence of tumor inhibited vaccine efficacy. For this work, we focused on tolerant preclinical tumor models. Vaccination of tolerant neu-N mice with alphaviral replicon particles expressing rat neu (neuET-VRP) failed to induce regression of established neu-expressing tumors. The inability of VRPs to induce regression in neu-N mice was due to a dominant role of the immunosuppressive tumor environment in these animals, as opposed to central deletion of tumor-specific lymphocytes. Accordingly, transfer of neu-specific lymphocytes into neu-N mice did not inhibit tumor growth. On the other hand, we demonstrated that myeloid-derived suppressor cells (MDSC) were a main mediator of suppression in neu-N mice. Depletion of MDSCs, along with provision of neu-specific lymphocytes and neuET-VRP vaccination, induced tumor regression in the majority of neu-N mice. We also identified other immunosuppressive mechanisms that suppressed anti-tumor immunity in neu-N mice. These included suppression by Treg cells, CD200 and IDO. As MDSCs were the main mediator of suppression following therapeutic vaccination, we evaluated genes important for their function. We found that MDSCs expressed NLRP3, a member of the inflammasome complex that generates IL-1[beta] and IL-18. While the NLRP3 inflammasome is known to enhance immunity in response to both microbial and non-microbial stimuli, its role in anti-tumor immunity is not known. We found that NLRP3 promoted the accumulation of MDSCs in the tumor following therapeutic dendritic cell (DC) vaccination. The decreased accumulation of MDSCs in Nlrp3-/- mice led to a fourfold improvement in survival compared to wild type mice after DC vaccination. These data establish an unexpected role for NLRP3 in impeding anti-tumor immunity and suggest novel approaches to improving cancer vaccines. In summary, our data suggest that current therapeutic vaccines are not effective due to the robust immunosuppressive mechanisms present in the tumor environment