Research ArticleExperimental Studies

Synergistic Benefit of Adoptive T Cells in Combination With Chemoradiotherapy Against Metastatic Prostate Cancer Cells

YUN-CHU SHEN, HUNG-JEN SHIH, CHI-CHIEN LIN, SHENG-HSIEN HUANG, SHENG-CHUAN WU, CHI-HAO HSIAO, SHAO-CHI CHIU, DER-YANG CHO, CHIN-PAO CHANG, YUEH PAN and PING-HSIAO SHIH
Anticancer Research July 2022, 42 (7) 3427-3434; DOI: https://doi.org/10.21873/anticanres.15829

Abstract

Background/Aim: Prostate cancer (PC) is one of the major diseases that affects male health and ranks as the second most frequent cancer in men worldwide. Although most newly-diagnosed PCs are well-differentiated tumors with a high cure probability, there are some patients with aggressive malignancies that show potential for recurrence and metastasis. Cytotoxic T lymphocytes are a specific immune effector cell population that mediates immune responses against cancer. Materials and Methods: In the present study, the cytotoxicity of peripheral blood mononuclear cells (PBMCs)-derived γδ T cells and cytokine-induced killer (CIK) cells in combination with chemoradiotherapy against PC cells was evaluated using Alamar blue cell viability and cell membrane permeability assays. Results: Advanced PC-3 cells, which were more resistant to docetaxel (Doc), also showed higher viability following pretreatment with radiation. The cell proliferation inhibition was significantly increased upon additional γδ T or CIK treatment. Furthermore, the proportion of apoptotic cells was significantly (p<0.05) increased in the Doc-γδ T cell co-treatment group as compared with the Doc or γδ T cell treated alone group. Conclusion: γδ T cell therapy may provide additional benefit compared to traditional chemoradiotherapy for PC treatment.

Key Words:

Prostate cancer (PC) is a common solid cancer and the second most common cause of cancer-related death (1). It is an androgen-dependent disease, including various classifications, different stages from localized, regional to metastatic disease. Radical prostatectomy or radiotherapy is the cornerstone for localized PC, but the risk of biochemical failure ranges from 40% to 70% due to adverse features, such as seminal vesicle invasion (SVI), positive surgical margin (PSM), and extracapsular extension (ECE) (2). Despite long-term survival under radical prostatectomy,radiotherapy, or androgen-deprivation therapy (ADT) in localized PC, some patients will finally develop into metastatic castration-sensitive prostate cancer (mCSPC), nonmetastatic castration-resistant prostate cancer (nmCRPC) or metastatic castration-resistant prostate cancer (mCRPC).

Different immunotherapeutic approaches, including dendritic cells (DC), chimeric antigen receptor (CAR) T-cell therapy targeting prostate cell surface antigens, passive immunotherapy using antibodies against prostate-specific membrane antigen (PSMA), immune checkpoint inhibitors (anti-PD-1/PD-L1 or anti-CTLA-4), are also being investigated as alternative cancer treatments (3). It has been reported that autologous peripheral blood mononuclear cells (PBMCs) activated by prostatic acid phosphatase and granulocyte-macrophage colony-stimulating factor (GM-CSF) that are then reinfused back to patients, could prolong overall survival by reducing tumor growth (4). Recently, a report showed that the peripheral blood from patients receiving anti-PD-1 antibody therapy is enriched in tumor-reactive CD4+ and CD8+ T cells and could be used to treat patients with cancer as tumor-infiltrating lymphocyte substitutes (5). In contrast, a phase III randomized clinical trial recently revealed that DCVAC/PCa combined with docetaxel (Doc) plus prednisone did not extend overall survival in patients with mCRPC (6). However, the unmet needs of research into novel therapeutics including targeted immunotherapy still hold much promise for improving the lives of patients with malignant cancers (7).

In this study, we simultaneously compared the cytotoxic effects of γδ T and CIK T cells in combination with chemoradiotherapy against metastatic PC cells that had never been reported. We found that irradiation enhanced the cytotoxicity in Doc-sensitive cells, and adoptive T cells in combination with Doc or irradiation would increase the proliferation inhibition against PC cells resistant to chemoradiotherapy. Furthermore, the significant apoptotic cell death was observed in Doc-γδ T cell co-treatment group. These data suggested that adoptive cytolytic T cell therapy might be an alternative approach for advanced PC treatment.

Materials and Methods

Cell lines, reagents, and chemicals. PC-3 bone human prostate carcinoma (BCRC No.60122), LNCaP supraclavicular lymph node human prostate carcinoma (BCRC No.60088) and DU145 brain human prostate carcinoma (BCRC No.60348) cell lines were all purchased from Bioresources collection and Research Center (Hsin Chu, Taiwan, ROC). Ficoll®Paque Plus was bought from GE Healthcare Life Sciences (Parramatta, New South Wales, Australia). X-VIVO 15 hematopoietic cell medium was purchased from Lonza (Basel, Switzerland). Recombinant human interferon-gamma was purchased from CellGenix (Portsmouth, NH, USA). Anti-CD3 antibody was purchased from TaKaRa Bio (Kusatsu, Shiga, Japan). Interleukin-1α was purchased from PeproTech (Rehovot, Israel). Recombinant human interleukin-2 (Proleukin®) was from Novartis (Basel, Switzerland). Zoledronic acid was purchased from Yungshin Pharm (Taipei, Taiwan, ROC). Ham’s F12K, RPMI 1640 as well as Minimum essential medium, fetal bovine serum, L-glutamine, alamarBlueTM cell viability reagent and TrypLE express enzyme solution were purchased from Gibco (ThermoFisher Scientific, Waltham, MA, USA). Carboxyfluorescein diacetate succinimidyl ester (CFSE) and 7-aminoactinomycin D (7-AAD) dyes were all purchased from BD Biosciences (San Jose, CA, USA). In the present study, all the cell culture materials were from the Good Manufacturing Practice (GMP)-grade companies.

Cell culture. The PC-3, LNCaP and DU145 human metastatic prostate adenocarcinoma cell lines were cultured in corresponding complete medium (90% basal medium containing 1.5 g/l sodium bicarbonate + 10-15% fetal bovine serum) in a humidified cell culture incubator (ThermoFisher Scientific) at 37°C and 5% CO2. The cells were detached using TrypLE Express Enzyme solution for cell passage.

PBMC isolation and culture. Healthy participants signed informed consent form for blood apheresis, which was approved by the China Medical University Hospital. About 20 ml of human venous blood sample was collected in a heparinized vial and mixed thoroughly. First, 4 ml of the density gradient solution was prepared in a 15 ml sterile tube, 1 ml of blood was carefully layered onto the density gradient solution (Ficoll®Paque Plus) and then centrifuged at 400 × g for 30 min at 20°C. The buffy coat layer was then carefully aspirated to another sterile tube. After mixing with phosphate-buffered saline (PBS), the white blood cells were centrifuged at 400 × g for 10 min at 20°C. Following aspiration of the supernatant, the cells were resuspended in red blood cells (RBC) lysis buffer and then centrifuged at 400 × g for 10 min. The cell pellet was suspended with X-VIVO 15 basal medium and cells were cultured at 37°C and 5% CO2 in a humidified incubator.

γô T and CIK cells induction and expansion. Induction and expansion of γδ T and CIK cells was performed as previously described (8, 9). In the beginning of the γδ T cell expansion (Day 0), the PBMCs were refed with X-VIVO 15 basal medium containing rh IL-2 (1,000 U/ml) and zoledronic acid (5 μM) for three days in a humidified cell culture incubator at 37°C and 5% CO2. On the third day, the medium was replaced with X-VIVO 15 basal medium containing rh IL-2 (1,000 U/ml). Fresh medium containing IL-2 (1,000 U/ml) was added every three days until the end of expansion (Day 14). In the CIK induction and expansion procedure, the PBMCs were cultured in fresh X-VIVO 15 basal medium containing IFN-γ (1,000 IU/ml) for 24 h on Day 0. On the first day, the medium was replaced with X-VIVO 15 basal medium containing anti-CD3 antibody (50 ng/ml), rh IL-1α (1 ng/ml), and rh IL-2 (1,000 U/ml). The medium was changed every three days. On the seventh day, cells were refed with X-VIVO 15 basal medium containing rh IL-2 (1,000 U/ml). The medium was replaced every three days until the end of cell expansion (Day 14).

Cell viability following chemoradiotherapy in combination with cytotoxic T cells against PC cells. PC cells were seeded in 96-well and treated as follows: (A) Doc (0-100 nM) alone group for 48 h, (B) pretreated with a total dosage of 10 Gray (Gy) (at 129.7 kV and 5.0 mA) X-ray radiation (CellRad System, Faxitron Bioptics, Tuson, AZ, USA), which was followed by the treatment with Doc (0-100 nM) for 48 h. (C) treated with irradiation and Doc, but also with the γδ T or CIK cells (combination immunotherapy). Cell proliferation was determined using the Alamar blue assay. Briefly, after the treatment, cells were washed, treated with alamarBlue™ reagent contained medium and incubated for three hours. The fluorescence (FL) value was measured at 590 nm with an excitation wavelength of 545 nm using an ELISA reader (SpectraMax iD3, Molecular Devices, San Jose, CA, USA). The cell viability is presented as: (FLtreat-FLcontrol)/FLcontrol* 100%.

Cell membrane permeability. In this study, the PC cells were stained with CFSE cell tracing dye before the day of the experiment. Then, cells were divided and treated as described above. After the treatment, the suspension and intact adherent cells were harvested. Then, the supernatant was centrifuged at 300 × g for 10 min and the cell pellet was resuspended gently in PBS containing 7-AAD dye (50 ng/μl). After a 10 min of incubation in the dark, the cells were analyzed by a flow cytometer (FACSCanto™ II, BD Biosciences, San Jose, CA, USA) and the cell death proportion was expressed as the CFSE/7-AAD double positive population. Data from >10,000 CFSE+ cells in each specimen were recorded.

Statistical analysis. All data were evaluated using SPSS 20.0 software (IBM, Armonk, NY, USA) and are shown as the mean±SE of the mean from at least three independent experiments. Differences between two groups were analyzed using one-way ANOVA, followed by a post hoc analysis. A p-value <0.05 was considered statistically significant.

Results

Characterization of CIK and γδ T cells. Figure 1 shows activation of γδ T and CIK T cells after 14 days of induction. The activation and expansion of CIK cells was performed using the standard protocol. PBMCs were induced with IFN-γ first and then treated with anti-CD3 antibody, IL-1α as well as IL-2’ and consecutively supplemented with IL-2 alone until the end of expansion. For γδ T cell induction, PBCMs were treated with zoledronic acid, which was followed by the administration of IL-2 alone to the end of expansion. The average proportion of CD3+CD56+ T cells was about 30-50% within the total cell population, while the proportion of CD3+/vγ9+ T cells was about >90% (Figure 1).

Figure 1.
Figure 1.

Cytokine-induced killer (CIK) and γδ T cell induction and expansion. For CIK expansion, PBMCs from consented healthy donors were initially exposed to rhIFN-γ (Day 0), followed by rhIL-2, rhIL-1α and anti-CD3 mAb (Day 1) every three days (Day 4). Subsequently, the medium was replaced with rhIL-2-containing medium every three days and the cells were harvested on Day 14. For γδ T expansion, PBMCs were exposed to zoledronic acid (5 μM) and rhIL-2 (1,000 U/ml) for 24 h on the Day 0. Subsequently, the medium was replaced with rhIL-2-containing medium (1,000 U/ml of reaction concentration) every three days and the cells were harvested on the Day 14. After induction, the phenotype of CIK (CD56+/CD3+) and γδ T (Vγ9+/CD3+) cells was recognized by flow cytometry.

Cytotoxic effects of Doc on metastatic PC cells. Next, we evaluated the effects of chemotherapy on the proliferation of PC cells. We found that Doc induced cytotoxicity in two PC cell lines in a dose-dependent manner (Figure 2A). PC-3 cells showed more resistance than DU145 cells and at Doc doses >50 nM DU145 cells were significantly (p<0.05) more sensitive than PC-3 cells. (Figure 2B). The IC50s for DU145 and PC-3 cells were ≅37±2.5 nM and 72±4.9 nM, respectively, following 48 h treatment.

Figure 2.
Figure 2.

Assessment of cytotoxicity of Doc on prostate cancer cells. PC cells were seeded in a 96-well plate and treated with the indicated concentrations of Doc (0-100 nM) for 48 h. At the end of incubation, the cell viability was analyzed using Alamar blue assay. (A) The morphology of PC cells treated with or without Doc. (B) Cell proliferation was normalized to control group. *Significant difference (p<0.05) between groups.

Cytotoxic effects of adoptive T cells on metastatic PC cells. Next, we investigated the cytotoxic potency of activated T cells against PC cells. Briefly, PC cells were co-cultured with various concentrations of γδ or CIK T cells for 48 h. Figure 3 shows the statistical analysis of the results when the ratio of effector (E) T cells versus target (T) PC cells (E/T) was 5:1. Interestingly, both PC-3 and DU145 cells were significantly sensitive to γδ T cells (p<0.05), whereas CIK T cells showed only partial inhibitory effects on the proliferation of PC cells.

Figure 3.
Figure 3.

Effects of adoptive T cells on the proliferation of PC cells. PC cells were seeded in a 96-well plate overnight. Then, the medium was replaced with T cell-containing complete medium. After 48 h of inoculation, cell viability was analyzed using Alamar blue assay. (A) The morphology of PC cells before and after treatment with the indicated T cells. (B) Cell proliferation normalized to control group. *Significant difference (p<0.05) as compared with the control group. #Significant difference (p<0.05) between treated groups.

Effect of irradiation in combination with immunotherapy or chemotherapy on the proliferation of metastatic PC cells. Furthermore, we investigated whether irradiation in combination with activated T cells or Doc showed synergistic effects on the proliferation of PC cells. Briefly, PC cells were pretreated with 10 Gy irradiation, which was followed by the treatment with the indicated concentrations (0-25 nM) of Doc for 48 h. When in combination with immunotherapy, the medium was replaced with T cell-containing medium after the irradiation and the 24 h of Doc treatment and then cultured for a further 24 h. Figure 4 shows the effect of these treatments on the proliferation of cells. In DU145 cells, the combination of Doc with both types of cytotoxic T cells significantly (p<0.05) enhanced the cytotoxic effects as compared with single treatment. Besides, cell proliferation was dramatically decreased in the irradiation pre-treatment groups. Similar results were also observed in PC-3 cells. Unexpectedly, triple treatment did not show a better response compared with dual treatment.

Figure 4.
Figure 4.

Effects of immunotherapy in combination with chemoradiotherapy on the proliferation of PC cells. The PC cells were seeded in a 96-well plate overnight. After 24 h of Doc treatment, the medium was replaced with T cell-containing complete medium. After 24 h of inoculation, cell viability was analyzed using the Alamar blue assay. In the irradiation study, PC cells were treated with 10 Gy of irradiation before the treatment with Doc and T cells. Cell proliferation was normalized to control group. *Significant difference (p<0.05) as compared with the Doc-treated groups. #Significant difference (p<0.05) as compared with group treated with CIK. *Significant difference (p<0.05) as compared with the group treated with γô T.

Enhancement of adoptive γδ T cells-mediated cytotoxicity in combination with chemotherapy against PC cells. Finally, we evaluated the effects of cytotoxic γδ T cells in combination with Doc on the permeability of PC-3 cells. The CFSE-stained PC-3 cells were pretreated with 25 nM Doc for 24 h, which was followed by the inoculation of γδ T cells for further 24 h. After treatment, the cells were harvested and stained with 7-AAD. Figure 5A shows the 7-AAD and CFSE doublestaining profile of cells following the treatments. The upper left panel is the non-CFSE-stained (NS) PC-3 cells group, and the upper right panel is CFSE-stained PC-3 cells as the control (Ctrl) group. The middle left and right panels are the methanol-treated PC-3 cells as the positive (Pos) control group and the Doc-treated PC-3 cell group, respectively. The lower left and right panels are the γδ T cell-treated PC-3 cell group and Doc and γδ T cell cotreated-PC-3 cell group, respectively. The data indicate significantly increased levels of late (7-AADbπght) and early apoptotic (7-AADdim) cells (p<0.05) in the Doc-γδ T cell co-treatment group as compared with the Doc or γδ T cell treated alone group (Figure 5B).

Figure 5.
Figure 5.

Apoptosis-inducing effects of γô T cells in combination with Doc on PC cells. CFSE-stained PC-3 cells were inoculated with γô T cells for 24 h after the 24 h of Doc treatment. The fluent and adherent cells were harvested and stained with 7-AAD after a PBS wash. (A) Illustration of γô T cell-induced cytotoxicity on PC-3 cells and the statistical analysis of apoptotic cell proportion from ten thousand of CFSE+-PC-3 cells (B). ^Significant difference (p<0.05) as compared with the Doc-treated group. *Significant difference (p<0.05) as compared with the γô T-treated group.

Discussion

Except for conventional chemotherapy using Doc, there are many novel therapeutic strategies (10). In the TROPIC and CARD studies, cabazitaxel, another taxane, was served as a second-line chemotherapy for patients with mCRPC (11, 12). Several new hormonal agents (such as enzalutamide, apalutamide, and darolutamide), which bind directly to the androgen receptor (AR) and inhibit the binding of androgens, AR nuclear translocation, and AR-mediated DNA binding, have also been tested in these patients. Enzalutamide was used in patients with mCSPC, nmCRPC, or mCRPC according to the AFFIRM, PREVAIL, PROSPER and ARCHES trials (13, 14). In the IMPACT study, sipuleucel-T, an active cellular immunotherapy, and a type of therapeutic cancer vaccine, consisting of autologous peripheral-blood mononuclear cells, antigen-presenting cells, prolonged overall survival of patients with mCRPC (15). Olaparib and rucaparib are a poly [adenosine diphosphate (ADP)-ribose] polymerase (PARP) inhibitors. In patients with mCRPC who had disease progression while receiving enzalutamide or abiraterone and who had mutations in homologous recombination repair genes (such as BRCA1, BRCA2, or ATM), olaparib prolonged progression-free survival and was associated with better measures of response and patient-reported outcomes than either abiraterone or enzalutamide (PROfound study) (16). In the phase II TRITON2 study, rucaparib has antitumor activity with a manageable safety profile in patients with mCRPC and BRCA1 or BRCA2 alteration (17). In the ALSYMPCA trial, a phase III, randomized, double-blind, placebo-controlled study, radium-223 dichloride (an alpha emitter) improved overall survival in patients with mCRPC (symptomatic bone metastases) (18). Although it is far to suggest that immunotherapy alone can dramatically challenge advanced PC, combination strategies are more reliable and promising (19). Recently, it was revealed that cancer patient-derived PBMC-activated CIK T cells have a stronger cytotoxic effect against some hematological cancer cell lines than γδ T cells (20). In addition, it has been reported that CIK T cells cocultured with dendritic cells, which were educated by immunogenic peptides derived from PC stem-like cells (PCSC), manifested significant in vitro cytotoxic activity against the PCSC as well as in vivo xenografts (21). However, it has been shown that prostasphere-derived PC cells with dominant stemness markers including CD133, NANOG, SOX2, and OCT4, were more resistant to γδ T cells than the parental PC cell line (22). Furthermore, it has also been suggested that Vγ9Vδ2 T cells not only acted as broadly tumor-specific killers but also presented MHC class I-restricted peptides, thereby triggering tumor-specific αβTCR CD8 T cell responses (23). To our best knowledge, our study is the first to report on the cytotoxicity of two types of adoptive T cells in combination with chemoradiotherapy against metastatic PC cells. We found that cytotoxicity was dramatically enhanced in Doc-sensitive DU145 cells by inoculation with CIK or γδ T cells, while only γδ T cells showed synergistic response in Doc-resistant PC-3 cells. In addition, although irradiation in combination with Doc or adoptive T cells alone enhanced the cytotoxicity, trimodal therapy did not show better responses, unexpectedly. Similar results were reported that Doc slightly induced the increase in the proportion of apoptotic cell for 48 h of incubation, while a significant increase in cell proportion in the sub-G1 phase of the cell cycle after 72 h was observed (24, 25). In the present study, we found that Doc in combination with γδ T cells dramatically increased the proportion of apoptotic cells after 48 h of treatment. The use of allogeneic T cells from healthy donors has many potential advantages over autologous approaches, such as convenient availability of qualified batches for patient treatment, time-saving for multiple cell activation, and decrease in the cost using an industrialized process instead of a personalized approach. However, allogeneic T cells may cause severe graft-versus-host response or may be rapidly eliminated by the host immune system (26).

Conclusion

In summary, the present study suggested that adoptive immunotherapy could be an alternative strategy and have synergistic benefits in combination with chemotherapy for metastatic PC treatment. Besides, based on our in vitro findings, γδ T cells would be given a priority for the treatment due to the limitation of purity in CIK T cells expansion. Thus, how to enhance the purity and promote the cytotoxicity would be the challenges of autologous immunotherapy in the future.

Acknowledgements

The present study was supported by grants from the Research Fund of the Department of Medical Research, China Medical University Hospital (grant no. DMR-107-153 and DMR-CELL-1809 to PHS), Taipei Municipal WanFang Hospital (grant no.109-wf-eva-28 to CHH) and Chuanghua Christian Hospital (grant no. Y_110_0436 to CPC and YP). We also appreciated Ya-Hsu Chiu for technological support.

Footnotes

  • Authors’ Contributions

    YCS, PHS, SCC, DYC and YP contributed to the conception and design of the study and prepared the manuscript. YCS, YP, and PHS performed the experiments and data analysis. HJS, CCL, SHH, CPC, and CHH reviewed the literature and interpreted the results. YP, HYC and PHS revised the manuscript. All Authors read and approved the final manuscript.

  • Conflicts of Interest

    The authors declare that they have no conflicts of interest in regard to this study.

  • Received May 16, 2022.
  • Revision received May 28, 2022.
  • Accepted June 1, 2022.

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Synergistic Benefit of Adoptive T Cells in Combination With Chemoradiotherapy Against Metastatic Prostate Cancer Cells
YUN-CHU SHEN, HUNG-JEN SHIH, CHI-CHIEN LIN, SHENG-HSIEN HUANG, SHENG-CHUAN WU, CHI-HAO HSIAO, SHAO-CHI CHIU, DER-YANG CHO, CHIN-PAO CHANG, YUEH PAN, PING-HSIAO SHIH
Anticancer Research Jul 2022, 42 (7) 3427-3434; DOI: 10.21873/anticanres.15829
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