The change of microenvironment induced by different thermal ablation in prostate and their clinical significances

doi:10.21203/rs.3.rs-1956866/v1

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The change of microenvironment induced by different thermal ablation in prostate and their clinical significances

https://doi.org/10.21203/rs.3.rs-1956866/v1

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Purpose: To compare the microenvironment change of three type thermal ablation: transperineal laser ablation (TPLA), radiofrequency ablation (RFA) and microwave ablation (MWA) application canine prostate and their clinical significances.

Methods: Nine beagles were randomly assigned to TPLA, RFA and MWA group. The ablation was operated in prostate. The level of cytokine (TNF-α, IL-12, TGF-β1 and IL-10) in serum was detected at four time point (before ablation, immediately, one week and one month after ablation). The positive cells of macrophages in the border of ablation lesions were detected.

Results: One week after ablation, the levels of pro-inflammatory cytokine (TNF-α) in the TPLA group was the highest, followed by the RFA group, and the MWA group was the lowest (159.11 ± 53.26 pg/ml, 129.57 ± 23.42 pg/ml, 53.65 ± 21.34 pg/ml, P＜0.03). However, one month later, the level of TNF-α had a continuous increase in TPLA group while which showed a significant decrease trend in other groups. The levels of anti-inflammatory cytokine (TGF-β1) in the TPLA group was significantly lower than other two groups (48.92 ± 48.67 pg/ml, 218.85 ± 27.56 pg/ml, 167.67 ± 45.67 pg/ml, P＜0.05). M1-like macrophages were dominant in TPLA group, and M2-like macrophages were dominant in RFA and MWA groups.

Conclusion: Microenvironment changes in the TPLA group were mainly pro-inflammatory, while anti-inflammatory responses were observed in the RFA and MWA groups.

Transperineal laser ablation

Radiofrequency ablation

Microwave ablation

Prostate

Microenvironment

Thermal ablation, as a mean of focal therapy, is an emerging alternatives treatment modality for prostate diseases while reducing the risk of side effects through preserving noncancerous tissues [1]. Transperineal laser ablation (TPLA), radiofrequency ablation (RFA) and microwave ablation (MWA) belong to thermal ablation. Previous literature has reported that TPLA, RFA and MWA were used in prostate cancer (PC) and benign prostatic hyperplasia (BPH), which have been proved to be safety and efficacy [2–6]. However, there is little known about the microenvironment change induced by thermal ablation and the differences among these technologies.

As is well known, thermal ablation induces local hyperthermic injury to target cells. The local and systemic inflammatory response may occur and inflammatory cytokine will be induced by thermal ablation [7–9]. Studies have reported that there were inflammatory infiltrates around the ablated lesion which include neutrophils, macrophages, dendritic cells (DCs), natural killer (NK) cells, as well as B cells and T cells that are specific to the ablated tissue [10–12]. Macrophages play a dual role in the inflammatory response, which were into classified two groups: “classically activated” pro-inflammatory M1 and “alternatively activated” anti-inflammatory M2. Depending on microenvironmental cues, these cells can stimulate inflammatory responses by secretion of pro-inflammatory cytokines like tumor necrosis factor (TNF)-α and interleukin (IL)- 12 or repair tissue and suppress immune responses by releasing high levels of anti-inflammatory cytokines like IL-10 and transforming growth factor (TGF)-β1 [13].

These study aims to explore the difference of microenvironment changes induced by thermal ablation in prostate by comparing the level of inflammatory cytokine and macrophages type in tissue.

Animals

Nine male adult beagles with a mating history were purchased from Dilepu Biomedical Co., Ltd. (Xian, China). These animals were randomly divided into the TPLA, RFA and MWA groups by a random number table. The mean age was 5.6 ± 0.4 years old, and the mean body weight was 16.2 ± 2.7 kg. The animal experiment protocol was approved by the Ethics Committee of the Centre for Drug Safety Evaluation of Zhengzhou University (Zhengzhou, China). All surgical procedures and experiments were performed under anesthesia in accordance with relevant guidelines and regulations, and every effort was made to minimize animal suffering.

Equipment

The equipments used were described in previous [14, 15]. The ultrasound system equipped with a transrectal dual-plane probe (E14CL4b) and contrasted tuned imaging mode (CnTI) (BK3000; B-K Medical Systems, Inc., Peabody, MA, USA) was used in this study.

The Echolaser X4 (Esaote SpA, Genoa, Italy) with an Nd:YAG laser emission source (at a wavelength of 1064 nm) was used for TPLA. The optical laser fibre with a diameter of 300 µm and a length of 20 cm was inserted through the sheath of the guidance needles, and the tip of the laser fibre was in direct contact with the tissue. For RFA, an LDRF-120S RFA instrument (Lead Electron Corp., Mianyang, China) and LDDJs3-0080100B radiofrequency electrodes were used, with a working tip of 1 cm. For MWA, an ECO-100E1 (MWA, Ecosystems Ltd., Leigh, UK) at a frequency of 2450 MHz and maximal output power of 100 W was utilized. The antenna (ECO-100AL2) had a 1.4 mm outer diameter and was 15 cm in length. Cold circulation inside the electrode and antenna was used to ensure the needle trunk temperature was maintained below 10°C.

Preoperative preparation

Food and water were withheld from the animals 12 hours before surgery. The abdomen and perineum of the beagles were waxed with a depilator. The use of glycerine enema for bowel cleansing is convenient for better observation of the prostate by transrectal probe. The protocol of anesthesia is as follow, which was similar to our previous literatures [14, 15]. Anesthesia was induced by the intramuscular injection of 8 mg/kg dexmedetomidine (Hengrui Pharmaceutical Co., LTD, Shanghai, China) and 2 mg/kg Zoletil 50 (Virbac Inc., Carros, France). After five minutes, 3mg/kg propofol (Xi 'an Libang Pharmaceutical Co., Ltd. Xi 'an, China) was injected intravenously. The beagle was then endotracheally intubated and connected to a respirator (Ruiwode life technology co. LTD, Shenzhen, China). Anaesthesia was maintained with of 2% ~ 3% aerosolized sevoflurane (Shanghai Hengrui Pharmaceutical Co., LTD, Shanghai, China) in oxygen during the procedure. All beagles were placed in a supine position and they body temperature was maintained with a warmed blanket. The animal-specific urinary catheter was placed into the bladder of each beagle.

Ablation

Ablation methods have been previously reported previous experiment [14]. The ablation in all the beagles was performed by a physician with over five years of ablation experience. Transrectal ultrasound (TRUS) examination was initially conducted for gross scanning of the prostate. The size of the prostate was measured, and then the puncture site in the perineum region was selected. Afterward, the energy transmitter was inserted into the prostate tissue through the perineum under TRUS guidance. The distance from the tip of the transmitter to the outer wall of the urethra, the rectum wall and the bladder floor was at least 8 mm, while the distance from the tip of the laser fibre to the bladder floor was at least 15 mm. The ablation process was continuously monitored via TRUS. For each beagle, ablation was performed twice to generate two ablation lesions on two lobes of the prostate. There were eighteen ablation lesions in total. The parameters of three ablation techniques were as follows: TPLA: 3W/1200J, 3W/600J, RFA and MWA: 30W/120s, 30W/60s.

After ablation, transrectal contrast-enhanced ultrasound (TR-CEUS) was conducted to image the ablated lesions. A bolus injection of 0.06 ml/kg SonoVue (Bracco Group, Milan, Italy) was administered through the indwelling catheter at the forearm vein, and then 5 ml of normal saline was used to flush the catheter. TR-CEUS examinations were repeated one week and one month later. The three biggest dimensions (a, b, c) of each ablation lesion were measured on the TR-CEUS images, and the volume (V) of the ablated lesions was calculated according to the formula as follow: V = 1/6 × π × (a × b × c).

Enzyme Linked Immunosorbent Assay

Blood samples were drawn for the forearm vein at four time points, including before ablation, immediately, one week and one month after ablation. After clotting and centrifugation (1000 rmp/min, 20 min), sera were fractionated and stored at -80℃ for standby application. The level of pro-inflammatory cytokine (TNF-α and IL-12) and anti-inflammatory cytokine (TGF-β1 and IL-10) in peripheral blood were analyzed using ELISA (Enzyme Linked Immunosorbent Assay) kit (all from Cloud-clone, Wuhan, China). A standard curve was established according to the manufacture’s instruction.

Immunohistochemistry

All prostate samples were fixed in 10% formalin solution for one week, and were sliced at transverse section with 5mm interval perpendicular to the urethra. Then, the sliced specimens were embedded in paraffin and sectioned at 5-µm thickness stained with haematoxylin and eosin (H&E) and immunohistochemistry.

The CD68 is a glycogen antigen expressed on macrophages, while CD163 and iNOS are expressed on the surface of M1 (pro-inflammatory) and M2 (anti-inflammatory) macrophages, respectively [16, 17]. Immunohistochemistry was performed as follow. The primary antibody used were as follows: anti-CD68 rabbit polyclonal antibody (ab125212, Abcam plc, Cambridge, UK), Anti-CD163 rabbit monoclonal antibody (ab182422, Abcam plc, Cambridge, UK), and Anti-iNOS rabbit polyclonal antibody (ab3523, Abcam plc, Cambridge, UK.). We analyzed five random fields under high-power magnification (× 40) for a minimum of three specimens for each parameter and performed scoring in a blinded fashion to remove observer bias. We calculated the percentage of positive cells (a ratio of stained and unstained cells) for each field and averaged for each specimen.

Statistical analysis

The SPSS 22.0 software (IBM, Armonk, NY, USA) was used to perform statistical analysis. All quantitative data were presented as means ± standard deviations (M ± SDs). The ANOVA was used to determine statistical significance among different groups. The significance level (P) on all statistical analysis was predefined at 0.05.

1、The level of inflammatory cytokines in serum were different among three groups after ablation.

Three beagles in each group received venous blood samples at four time points as described above. The serum levels of pro-inflammatory cytokine (TNF-α and IL-12) and anti-inflammatory cytokine (TGF-β1 and IL-10) were detected by ELISA.

Before ablation, there was no difference about the level of inflammatory cytokines in serum among three groups. After ablation, the level of TNF-α increased gradually after ablation in three groups. One week after ablation, the levels of the three groups were different, among which the TPLA group was the highest, followed by the RFA group, and the MWA group was the lowest (159.11 ± 53.26 pg/ml, 129.57 ± 23.42 pg/ml, 53.65 ± 21.34 pg/ml, P = 0.03). From one week to one month after ablation, the level of TNF-α showed a different trend in TPLA and RFA, the former had a continuous increase while the latter showed a significant decrease trend. The level of IL-12 in serum did not change significantly before and after ablation in the three groups.

The level of anti-inflammatory cytokines (TGF-β1 and IL-10) showed no significant change over time in the MWA group, while there was a decreasing trend after ablation in TPLA and RFA group after ablation. However, the RFA group showed a rebound and increased one week later, while the TPLA group continued to decrease. At one month after ablation, the levels of TGF-β1 in the TPLA group were significantly lower than those in the RFA group and MWA group (48.92 ± 48.67 pg/ml, 218.85 ± 27.56pg/ml, 167.67 ± 45.67pg/ml, P = 0.01) (Fig. 1).

2、The positive percentages of macrophage cells was different among three groups one month after ablation.

There were many macrophage cells in the border of ablation lesions in three groups. The percentages of CD68-positive cells in TPLA group, RFA group, and MWA group were 95 ± 79% /high-power field (HPF), 70 ± 55%/HPF and 35 ± 21%/HPF (P༜0.05), respectively. The percentage of iNOS positive cells in TPLA group was significantly higher than RFA and MWA group (48 ± 9%/HPF VS 18 ± 8%/HPF,15 ± 4%/HPF, P༜0.05)。The percentage of CD163 positive cells in RFA group was significantly higher than TPLA and MWA group (80 ± 7%/HPF VS 49 ± 10%/HPF, 64 ± 9%/HPF, P༜0.05) (Fig. 2 and Fig. 3)。

3、Dynamic changes in the volume of the thermal ablation lesions in three groups

TR-CEUS was used to dynamically observe the changes in the volume of thermal ablation lesions. The results showed that the volume of ablation lesions in TPLA group increased gradually with time, increasing by 320% ± 167% (3W/600J) and 110% ± 42% (3W/1200J) one month after TPLA. The ablation lesions’ volume in RFA and MWA groups increased slightly one week after ablation, and decreased obviously one month after ablation. The volume in RFA group decreased by 32% ± 6% (30W/60s) and 42% ± 13% (30W/120s) at one month after ablation, respectively, while that in MWA group decreased by 88% ± 10% (30W/60s) and 138% ± 18% (30W/120s) one month after ablation (Fig. 4).

The changes in microenvironment after thermal ablation were complicated. First, heat-ablated lesions in tissue can be thought of as having three zones: the central zone, which is immediately beyond the application tip and which undergoes ablation-induced coagulative necrosis; the peripheral or transitional zone of sublethal hyperthermia, which mostly occurs from thermal conduction of the central area that is either undergoing apoptosis or recovering from reversible injury; and the surrounding tissue that is unaffected by ablation [18]. In the transitional zone, which occurs adjacent to the central area of coagulative necrosis, studies have reported inflammatory infiltrates that include neutrophils, macrophages, dendritic cells (DCs), natural killer (NK) cells, as well as B cells and T cells that are specific to the ablated tissue[10–12]. Besides, the systemic response also happens after thermal ablation [19]. Evidence indicates that hyperthermic destruction causes the release of a large population of inflammatory cytokines, which may elicit immune responses against tumor [20].

In this study, inflammatory responses were observed after thermal ablation in all three groups. The level of pro-inflammatory cytokine (TNF-α) increased gradually after ablation. However, there are some differences among different ablation technologies. One week after ablation, the level of TNF-αin TPLA group being the highest, the MWA group being the lowest, and the RFA group being in the middle, which was similar to the results of previous ablation studies on liver [21]. Further observation showed that the level of TNF-α decreased after one week in both RFA and MWA groups, while it still continued to increase in TPLA group. The level of TGF-β1, which is an anti-inflammatory cytokine was decreased in the TPLA group at different time points, while it decrease in the RFA group immediately after ablation, and then increased after one week. The results of IHC in the border of ablation lesions showed that the TPLA group was dominated by M1-like macrophages, while the RFA and MWA groups were dominated by M2-like macrophages.

The status of microenvironment may explain the differences dynamic change of ablation lesions’ volume in the three groups. The volume of in TPLA group increased gradually with the prolonging of time in one month. While the volume in RFA and MWA group shrank at one month after ablation. Although there some similar reports about the change of volume after thermal ablation in other organs [21–25], the exact mechanism has never been clear. We have previously reported that vascular permeability of microcirculation and micro vascular thrombosis around the ablation lesions may be involved in the progress of tissue damage, and then volume of coagulated necrosis gradually expanded with time[15]. Besides, maybe the changes of mircroenvironemt and inflammatory response were involved in the volume change. Pro-inflammatory cytokines stimulated sublethal or active cells in the transitional zone to further release inflammatory response factors, which further led to the expansion of necrosis range[19]. TGF-β1 is produced by M2-like macrophage cells and played an important role in anti-inflammatory repair [26], which increased in RFA and MWA groups.Besides, TGF-β1 was considered a central mediator of injury repair and fibrosis, inducing extracellular matrix production and proliferation of myofibroblasts. So the anti-inflammatory repair play a role in the volume shrank.

Combined with the changes of serum inflammatory cytokines in the blood of the three groups and the results of immunohistochemistry, the inflammatory response after TPLA was the most severe and lasted the longest, and the main pro-inflammatory response was within one month. However, in the RFA and MWA groups, anti-inflammatory repair was the main inflammatory response after one week, TPLA, RFA and MWA all belong to thermal ablation technology, why induced such a difference? A prior study has reported that there was greater periablational rim thickness and serum IL-6 levels for hepatic RFA (20W/2–3minutes) versus MWA (10W/7–12 minutes) performed with variable ablation protocols in animals [27]. For the same ablation device, different parameters of RFA in normal liver which can result in similarly-sized ablation zones (6.1 ± 0.1mm) induced different degrees of inflammatory response and different width of the inflammatory response zone [28]. The lower power and longer duration(60℃/10min ) induced more sever inflammatory response than high power and short duration (90℃/2min) [29]. For the MWA, previous literature reported that the high power and short duration (20w/15s) induced fewer macrophage cells in the peripheral ablation lesions than the low power and long duration (5w/2min) [30]. So, for the some approaches, such as lower power ablation with longer heating to achieve greater ablation sphericity, may increase periablational inflammation, as we demonstrate [31]. One potential explanation for this difference between different parameters is that the duration. For the higher power, heat is being generated throughout the target zone from the interaction of application with tissues directly. However, for the lower energy, long duration was needed, and heat is being generated near the application, so heating in the surrounding of the ablation zone is achieved by thermal conduction. This thermal tissue gradient may create a wider rim of periablational tissue that is exposed to lower nonlethal levels of heating and induced more serves inflammatory response [32, 33]. In this animal experiment, the duration of three types of ablation were different, which was longer in TPLA group (200s and 400s) than that in RFA and MWA group (60s and 120s). So this may be the reason of the serves inflammtory response in TPLA group. This suggests that the attention should be paid to the inflammatory response and anti-inflammatory drugs should be added appropriately to prevent the harm of excessive inflammatory reaction to the body and avoid the enlargement of the ablation lesions in the clinical application of TPLA. This is only an animal experiment, and whether there is similar situation in specific clinical application has not been studied yet. However, recent literature on TPLA treatment of BPH has reported that anti-inflammatory drugs represented by dexamethasone have been applied after surgery [5, 6]. In addition, studies have shown that inflammation is accompanied with the activation of a large number of immune cells in the body [34]. So, in the case of laser ablation of tumor patients, whether the inflammatory response in the body indicates that the "cold tumor" will be stimulated to the "hot tumor" and then sensitive to immunotherapy, or whether the TPLA combined with immunotherapy will have better clinical effects. So all these speculations need to be clinically verified and further studied.

There were some limitations to this study. Firstly, the sample size of animals in each group is small. Secondly, the observation time is only up to one month, which cannot predict the changes over longer period. Thirdly, this study only observed the normal beagles, not the tumor model underwent thermal ablation. So, further investigation is needed.

ETHICAL APPROVAL

The study protocol was approved by the Ethics Committee of the Centre for Drug Safety Evaluation of Zhengzhou University (Zhengzhou, China). The ethics committee of this organization consists of animal welfare experts.

AUTHOR CONTRIBUTIONS

(I) Conception and design: R Liu, L Zhang; (II) Administrative support: H Cao, L Zhang; (III) Provision of study materials or patients: S Duan, Z li; (IV) Collection and assembly of data: R Liu, Y Li, N Li; Y Xing; (V) Data analysis and interpretation: R Liu, G Cao, N L; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

CONFLICT OF INTEREST STATEMENT

The authors declare that they have no conflict of interest.

FUNDING

Supported by the National Key Research and Development Program of China (2018YFC0114606) and Medical science and technology of Henan Province（LHGJ20210007）

STATEMENT

The study was reported in accordance with ARRIVE guidelines

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No competing interests reported.

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The change of microenvironment induced by different thermal ablation in prostate and their clinical significances

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Abstract

Figures

Introduction

Materials And Methods

Animals

Equipment

Preoperative preparation

Ablation

Enzyme Linked Immunosorbent Assay

Immunohistochemistry

Statistical analysis

Results

3、Dynamic changes in the volume of the thermal ablation lesions in three groups

Discussion

Declarations

References

Additional Declarations

Supplementary Files

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