Table 2.
Summary of IRE studies investigating the effects on the immune system.
| Species | Authors | Interventions (n) | Cancer Types | Key Findings |
|---|---|---|---|---|
| Human | Guo et al., 2021 [112] | IRE (11) | Hepatocellular carcinoma | The peripheral neutrophils and monocytes increased by day 1 after IRE and returned to baseline at day 7, while CD4+ T cells decreased by day 1 followed by an increase in the next days. CD8+ T cells remained unchanged. Treg cells decreased from day 3 to 14 followed by an increase at one month. |
| He et al., 2019 [104] | IRE (34) | Locally advanced pancreatic cancer | The peripheral CD4+ T cells, CD8+ T cells, and NK cells decreased by day 3 after IRE followed by an increase at day 7, while a reverse trend was shown for Treg cells. IL-6 and IL-10 levels increased at day 3 after IRE followed by a decrease at day 7. IL-2 increased from day 3 to day 7. Concentrations of IFN-γ and TNF did not significantly change. Increased numbers of CD4+ T cells, CD8+ T cells, and NK cells or decreased Treg cells were associated with longer OS. |
|
| Pandit et al., 2019 [97] | IRE/pancreatectomy (11/4) | Locally advanced pancreatic cancer | The peripheral Treg populations increased day 1 to 3 and decreased from day 3 to 5 in the IRE group compared to increases on day 1 to 3 as well as increases on day 3 to 5 in the pancreatectomy group. | |
| Scheffer et al., 2019 [113] | IRE (10) | Locally advanced pancreatic cancer | Pre- and post-IRE peripheral levels of CD4+ and CD8+ T cells did not change. At 2 weeks following IRE, a decrease in total Tregs was observed, as well as in aTregs and in resting Tregs, accompanied by a transient increase in both peripheral CD4+PD-1+ and CD8+PD-1+ T cell numbers. | |
| Beitel-White et al., 2019 [114] | IRE (8) | Pancreatic cancer (stage III) | An increase in current change during IRE treatment was associated with decreases in Treg populations 24 h after IRE. Changes in current above 20A induced decreased Treg populations. Further, a trend was shown towards increased survival for the group of patients with a >2% decrease in Treg cells. | |
| Swine | Fujimori et al., 2021 [115] | IRE/microwave ablation | Normal lung | Fifty percent of blood vessels and collagen were intact 2 days after IRE compared to 0% after microwave ablation. Further, the number of CD3+ T cells increased more after IRE than after microwave ablation. |
| Rabbit | Lee et al., 2012 [98] | IRE | Hepatocellular carcinoma | Examinations of non-IRE treated organs, e.g., the lungs, showed no metastases in the IRE group, while all 15 rabbits in the control group had lung metastases. IRE-treated tumors showed increased levels of CD30-positive cells, mainly in the zone between viable and dead tumor. |
| Mouse | Dai et al., 2021 [99] | IRE | Hepatocellular carcinoma | IRE increased the percentage of IFN-γ+ CD8+ T cells in splenocytes and increased tumor infiltration of CD8+ T cells. On day 7, reductions of both peripheral and intratumoral Treg cells and PD-1+ T cells were shown. Mice rejected the tumor re-challenge with hepatocellular carcinoma cells following IRE. |
| He et al., 2020 [95] | IRE | Pancreatic cancer | IRE resulted in longer survival and more proliferating CD8+ T cells in the tumor and spleen. Both memory and effector CD8+ T cells were increased in the tumor and the tumor-draining lymph node regions. The viable region showed increased microvessel density and softening of the extracellular matrix. Mice that were re-challenged with pancreatic cancer cells after IRE rejected the tumor challenge. |
|
| Chen et al., 2017 [116] | IRE | Hepatocellular carcinoma | IRE induced a change in the T helper 1/T helper 2 cell ratio towards T helper 1 dominance, an increase in macrophage tumor infiltration, and an increase in IFN-γ and IL-2 compared to controls. | |
| White et al., 2018 [117] | IRE or cryoablation | Pancreatic cancer | IRE induced a higher number of tumor-infiltrating T cells and macrophages at 12 and 24 h after treatment. | |
| Bulvik et al., 2016 [94] | IRE/radiofrequency ablation (82/82) | Normal liver Hepatocellular carcinoma |
The tumor infiltration of neutrophils and macrophages was increased in both groups; however, it was greater in the radiofrequency ablation group. In the IRE group, the infiltration of the neutrophils and macrophages extended along the preserved vessels within the ablation zone. At 72 h, persistent vessels in the ablation zone were seen for IRE-treated mice only. IL-6 levels peaked after 6 h, 3 and 10 times higher than controls (radiofrequency ablation and IRE, respectively). By 24 h, no elevations were seen. Radiofrequency ablation of the liver slowed the growth of an untreated tumor, while IRE resulted in greater reduction in tumor growth. Three days after treatment, the number of CD3+ cells was elevated in the untreated tumor in both groups. |
|
| Neal et al., 2013 [100] | IRE | Renal carcinoma | IRE-treated immunocompetent mice showed robust T-cell infiltration at the zone between viable and dead tumors. Further, IRE-treated immunocompetent mice showed a greater treatment response than did immunodeficient mice. | |
| José et al., 2012 [93] | IRE | Pancreatic cancer | IRE was not found to activate apoptotic cell death measured by caspase-3 positive cells in the tumors. The vascular architecture of the tumor was disrupted from day 1 after IRE and onward. | |
| Al-sakere et al., 2007 [101] | IRE | Sarcoma | No tumor infiltration of CD4+ or CD8+ T lymphocytes, macrophages, APCs, dendritic cells were observed 2 and 6 h after IRE. | |
| Li et al., 2012 [105] | IRE/sham surgery/resection/control (28/28/28/28) | Osteosarcoma | IRE and resection increased the percentages of the peripheral CD3+ and CD4+ cells, as well as the CD4+/CD8+ ratio 7 days after treatment. A more rapid and prolonged increase was seen in the IRE group. IRE and resection caused decreases in IL-10 from day 3 to 21. The percentage of INF-γ-positive splenocytes was higher in the IRE group. | |
| Rat | He et al., 2021 [88] | IRE | Pancreatic cancer | IRE caused increased levels of HMGB1, HSP70, and calreticulin. Seven days after IRE, higher frequencies of M1 macrophages in the tumor and a regional lymph node were seen compared to controls, while a decrease in M2 macrophages was seen in the tumor. |
| Cell | He et al., 2021 [88] | IRE | Pancreatic cancer | HMGB1 were shown to induce M1 macrophage polarization via receptor of advanced glycation end-product. Further, HMGB1 could enhance the phagocytosis of dying tumor cells by macrophages. |
| Shao et al., 2019 [8] | IRE/thermal therapy/cryosurgery | Melanoma | IRE caused the greatest protein release, second lowest denaturation rate of the released protein (30%), the most TLR2 (a measure of the relative antigen content of the released protein) release, and the strongest T cell response. | |
| Zhao et al., 2019 [87] | IRE/radiotherapy | Pancreatic cancer Melanoma |
IRE increased the ATP and HMGB1 levels by 11 and 13 fold, respectively, compared to radiotherapy, which did not cause the release of ATP and HMGB1. IRE: Cells increased the expression of makers for DC activation/maturation by 51–72%, compared to non-IRE treated cells. Radiotherapy: Cells did not increase the expression of makers for DC activation/maturation, compared to non-radiotherapy treated cells. IRE increased the ATP and HMGB1 levels by 8 and 9 fold, respectively. |
|
| Goswami et al., 2017 [118] | IRE/thermal shock/chemical poration | Triple negative breast cancer | IRE caused upregulation of IL-6 and TNF, while thymic stromal lymphopoietin was down-regulated. Cancer cells treated with thermal shock or chemical poration showed no down-regulation of thymic stromal lymphopoietin. |
APC, antigen-presenting cell; aTreg, activated Tregs; DC, dendritic cell; IL, interleukin; IRE, irreversible electroporation; Treg, regulatory T cell; TRP2, Toll-like receptor 2.