Figure 2.

Cryo-immunotherapy: the patient with metastases is treated with local cryoablation of one of them combined with systemic immunotherapies. (A) Administration of low dose toll like receptor (TLR) agonists will cause the activation and maturation of DCs. (B) Cryoablation of a tumor induces tumor necrosis and release of tumor antigens into the surrounding milieu, which are taken up by mature DCs located near the tumor or TDLN. These DCs present tumor antigens to naive T-cells in the TDLN in the presence of agonistic antibodies (for example, CD27) leading to enhanced activation and differentiation into effector T-cells. (C) The effector T-cells thus generated will migrate to the cryoablated tumor site encountering the tumor cells and DCs presenting tumor antigens on their surface MHC molecules. Introduction of checkpoint inhibitors (for example, anti-CTLA-4 and anti-PD-1) will allow the T-cells to execute tumor cell killing without being inhibited by the checkpoint signaling. Eventually, the effector T-cells with blocked checkpoint molecules will also migrate to the distant metastasized tumor sites, leading to the regression of metastases. TLR, toll like receptor; DC, dendritic cell; TDLN, tumor draining lymph node; TCR, T-cell receptor; MHC, major histocompatibility complex.