Cryoablation and Immunotherapy: An Enthralling Synergy to Confront the Tumors

Abstract

Treatment of solid tumors by ablation techniques has gained momentum in the recent years due to their technical simplicity and reduced morbidity as juxtaposed to surgery. Cryoablation is one of such techniques, known for its uniqueness to destroy the tumors by freezing to lethal temperatures. Freezing the tumor locally and allowing it to remain in situ unleashes an array of tumor antigens to be exposed to the immune system, paving the way for the generation of anti-tumor immune responses. However, the immune responses triggered in most cases are insufficient to eradicate the tumors with systemic spread. Therefore, combination of cryoablation and immunotherapy is a new treatment strategy currently being evaluated for its efficacy, notably in patients with metastatic disease. This article examines the mechanistic fabric of cryoablation for the generation of an effective immune response against the tumors, and various possibilities of its combination with different immunotherapies that are capable of inducing exceptional therapeutic responses. The combinatorial treatment avenues discussed in this article if explored in sufficient profundity, could reach the pinnacle of future cancer medicine.

Keywords: ablation; cryo; freezing; immunotherapy; treatment; tumors.

Copyright © 2019 Yakkala, Chiang, Kandalaft, Denys and Duran.

Figures

Figure 1

Mechanisms of cell death and immunologic responses induced by cryoablation. (A) Cells in the core of the ablation zone are subjected to lethal temperatures at rapid freezing rates, resulting in the generation of extra and intracellular ice crystals. Cells adjacent to the core zone undergo moderate or low freezing rates. This permits the cells to lose intracellular water by exosmosis in response to the formation of extracellular ice crystals resulting in cellular dehydration and shrinkage. In contrast, cells in the core zone cannot undergo exosmosis due to rapid freezing rates and thus, form intracellular crystals. Both intra and extracellular ice crystals cause mechanical damage to the cells. (B) During the thawing phase, the small intracellular ice crystals, due to their thermodynamic instability, fuse to form larger intracellular crystals (re-crystallization) that enhances the mechanical damage to the cell membranes and intracellular organelles. (C) Post-thawing, mechanically damaged cells die by necrosis and release their contents into the surrounding milieu. Cells that have undergone exosmosis swell and burst due to osmotic shock. Cells in the utmost periphery of the ablation zone exposed to sub-lethal temperatures undergo apoptosis, releasing apoptotic bodies. Antigens released from necrotic cells upon uptake by antigen presenting cells like DCs, induce co-stimulatory signals that would result in the generation of anti-tumoral T-cell responses. In contrast, antigen uptake by DCs in the form of apoptotic bodies imprints immune tolerance or anergy on T-cells due to the non-induction of co-stimulatory signals on DCs. DC, Dendritic cell.

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.