Differential Cytokine Profiles in Prostate Cancer Under Treatment: Implications for Prognosis and Synergistic Therapy Design
Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Study Design and Subjects
2.2. Blood and Urine Collection
2.3. Human Cytokine Panel
2.4. Statistical Analysis
3. Results
3.1. Demographics
3.2. Urine and Plasma Cytokines
3.3. Cytokine Levels Associated with Treatment Type
3.4. Cytokine Levels Associated with Visit Number
3.5. Cytokine Levels Associated with Treatment Type and Visit Number
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Dejonckheere, C.S.; Caglayan, L.; Glasmacher, A.R.; Wiegreffe, S.; Layer, J.P.; Nour, Y.; Scafa, D.; Sarria, G.R.; Spohn, S.; Essler, M.; et al. Prostate-specific antigen kinetics after stereotactic body radiotherapy for localized prostate cancer: A scoping review and meta-analysis. Radiother. Oncol. 2025, 202, 110642. [Google Scholar] [CrossRef]
- Lazarovich, A.; Viswanath, V.; Dahmen, A.S.; Sidana, A. A narrative clinical trials review in the realm of focal therapy for localized prostate cancer. Transl. Cancer Res. 2024, 13, 6529–6539. [Google Scholar] [CrossRef] [PubMed]
- Sidana, A.; Lazarovich, A.; Tayebi, S.; Huron, A.; Blank, F.; Tobler, J.; Verma, S.; Hsu, W.W. Prostate ablation for the management of localized prostate cancer. Urol. Oncol. 2025, 43, 194.e9–194.e17. [Google Scholar] [CrossRef] [PubMed]
- Borzillo, V.; Scipilliti, E.; Pezzulla, D.; Serra, M.; Ametrano, G.; Quarto, G.; Perdonà, S.; Rossetti, S.; Pignata, S.; Crispo, A.; et al. Stereotactic body radiotherapy with CyberKnife® System for low- and intermediate-risk prostate cancer: Clinical outcomes and toxicities of CyPro Trial. Front. Oncol. 2023, 13, 1270498. [Google Scholar] [CrossRef]
- Coelho, K.B.C.A.; Wosniaki, D.K.; Pereira, J.L.; Luz, M.; Albrecht, L.; Nardin, J.M.; Aoki, M.N.; Reis, L.O.; Dos Reis, R.B.; Zanette, D.L. Comparative Analysis of Cytokine Expression Profiles in Prostate Cancer Patients. Biology 2025, 14, 505. [Google Scholar] [CrossRef]
- Foldi, J.; Blenman, K.R.M.; Marczyk, M.; Gunasekharan, V.; Polanska, A.; Gee, R.; Davis, M.; Kahn, A.M.; Silber, A.; Pusztai, L. Peripheral blood immune parameters, response, and adverse events after neoadjuvant chemotherapy plus durvalumab in early-stage triple-negative breast cancer. Breast Cancer Res. Treat. 2024, 208, 369–377. [Google Scholar] [CrossRef]
- Guo, D.; Qin, L.; Sun, J.; Li, K.; Zang, C.; Wang, Q.; Qiao, W.; Liu, B.; Zhao, Y.; Zhang, Y. Dynamic Changes of Cytokine Profiles and Their Correlation with Tumor Recurrence Following Thermal Ablation in Hepatocellular Carcinoma. Technol. Cancer Res. Treat. 2023, 22, 15330338231190644. [Google Scholar] [CrossRef] [PubMed]
- Shin, D.; Kim, J.; Lee, S.; Chae, M.S. Impact of Perioperative Lidocaine on Neutrophil Extracellular Trapping and Serum Cytokines in Robot-Assisted Radical Prostatectomy: Randomized Controlled Study. Medicina 2024, 60, 1452. [Google Scholar] [CrossRef]
- Chakravarty, D.; Ratnani, P.; Huang, L.; Dovey, Z.; Sobotka, S.; Berryhill, R.; Merisaari, H.; Al Shaarani, M.; Rai, R.; Jambor, I.; et al. Association between Incidental Pelvic Inflammation and Aggressive Prostate Cancer. Cancers 2022, 14, 2734. [Google Scholar] [CrossRef]
- Turner, M.D.; Nedjai, B.; Hurst, T.; Pennington, D.J. Cytokines and chemokines: At the crossroads of cell signalling and inflammatory disease. Biochim. Biophys. Acta 2014, 1843, 2563–2582. [Google Scholar] [CrossRef]
- Briukhovetska, D.; Dörr, J.; Endres, S.; Libby, P.; Dinarello, C.A.; Kobold, S. Interleukins in cancer: From biology to therapy. Nat. Rev. Cancer 2021, 21, 481–499. [Google Scholar] [CrossRef]
- Aliyu, M.; Zohora, F.T.; Anka, A.U.; Ali, K.; Maleknia, S.; Saffarioun, M.; Azizi, G. Interleukin-6 cytokine: An overview of the immune regulation, immune dysregulation, and therapeutic approach. Int. Immunopharmacol. 2022, 111, 109130. [Google Scholar] [CrossRef]
- Jaén, M.; Martín-Regalado, Á.; Bartolomé, R.A.; Robles, J.; Casal, J.I. Interleukin 13 receptor alpha 2 (IL13Rα2): Expression, signaling pathways and therapeutic applications in cancer. Biochim. Biophys. Acta Rev. Cancer 2022, 1877, 188802. [Google Scholar] [CrossRef]
- Huangfu, L.; Li, R.; Huang, Y.; Wang, S. The IL-17 family in diseases: From bench to bedside. Signal Transduct. Target. Ther. 2023, 8, 402. [Google Scholar] [CrossRef] [PubMed]
- Zhou, R.; Feng, Y.; Ye, J.; Han, Z.; Liang, Y.; Chen, Q.; Xu, X.; Huang, Y.; Jia, Z.; Zhong, W. Prediction of Biochemical Recurrence-Free Survival of Prostate Cancer Patients Leveraging Multiple Gene Expression Profiles in Tumor Microenvironment. Front. Oncol. 2021, 11, 632571. [Google Scholar] [CrossRef] [PubMed]
- Mughees, M.; Kaushal, J.B.; Sharma, G.; Wajid, S.; Batra, S.K.; Siddiqui, J.A. Chemokines and cytokines: Axis and allies in prostate cancer pathogenesis. Semin. Cancer Biol. 2022, 86, 497–512. [Google Scholar] [CrossRef]
- Palermo, B.; Bottero, M.; Panetta, M.; Faiella, A.; Sperduti, I.; Masi, S.; Frisullo, G.; Foddai, M.L.; Cordone, I.; Nisticò, P.; et al. Stereotactic Ablative Radiation Therapy in 3 Fractions Induces a Favorable Systemic Immune Cell Profiling in Prostate Cancer Patients. Oncoimmunology 2023, 12, 2174721. [Google Scholar] [CrossRef]
- Mao, C.; Ding, Y.; Xu, N. A Double-Edged Sword Role of Cytokines in Prostate Cancer Immunotherapy. Front. Oncol. 2021, 11, 688489. [Google Scholar] [CrossRef]
- Kane, N.; Romero, T.; Diaz-Perez, S.; Rettig, M.B.; Steinberg, M.L.; Kishan, A.U.; Schaue, D.; Reiter, R.E.; Knudsen, B.S.; Nickols, N.G. Significant changes in macrophage and CD8 T cell densities in primary prostate tumors 2 weeks after SBRT. Prostate Cancer Prostatic Dis. 2023, 26, 207–209. [Google Scholar] [CrossRef] [PubMed]
- Miljanic, M.; Montalvo, S.; Aliru, M.; Song, T.; Leon-Camarena, M.; Innella, K.; Vujovic, D.; Komaki, R.; Iyengar, P. The Evolving Interplay of SBRT and the Immune System, along with Future Directions in the Field. Cancers 2022, 14, 4530. [Google Scholar] [CrossRef]
- Singh, J.; Sohal, S.S.; Lim, A.; Duncan, H.; Thachil, T.; De Ieso, P. Cytokines expression levels from tissue, plasma or serum as promising clinical biomarkers in adenocarcinoma of the prostate: A systematic review of recent findings. Ann. Transl. Med. 2019, 7, 245. [Google Scholar] [CrossRef]
- Aghaei, M.; Bahreiny, S.S.; Mahdizade, A.H.; Abbasi, A.; Magharati, A.; Yousefi-Avarvand, A. “Cytokine-Mediated tumor sensitization: Mechanistic frameworks and therapeutic opportunities in cancer Immunotherapy”. Clin. Exp. Med. 2026, 26, 135. [Google Scholar] [CrossRef] [PubMed]
- Bernal, A.; Bechler, A.J.; Mohan, K.; Rizzino, A.; Mathew, G. The Current Therapeutic Landscape for Metastatic Prostate Cancer. Pharmaceuticals 2024, 17, 351. [Google Scholar] [CrossRef] [PubMed]
- Gunturu, D.R.; Hassan, M.; Bedi, D.; Datta, P.; Manne, U.; Samuel, T. Unlocking the Potential of Therapy-Induced Cytokine Responses: Illuminating New Pathways in Cancer Precision Medicine. Curr. Oncol. 2024, 31, 1195–1206. [Google Scholar] [CrossRef]
- Burzinskis, E.; Janulaityte, I.; Jievaltas, M.; Skaudickas, D.; Burzinskiene, G.; Dainius, E.; Naudziunas, A.; Vitkauskiene, A. Inflammatory markers in prostate cancer: Potential roles in risk stratification and immune profiling. J. Immunotoxicol. 2025, 22, 2497776. [Google Scholar] [CrossRef]
- D’Auria, F.; Valvano, L.; Calice, G.; D’Esposito, V.; Cabaro, S.; Formisano, P.; Bianchino, G.; Traficante, A.; Bianculli, A.; Lazzari, G.; et al. Hypofractionated radiotherapy with simultaneous integrated boost for localized prostate cancer patients: Effects on immune system and prediction of toxicity. Front. Immunol. 2024, 15, 1457839. [Google Scholar] [CrossRef] [PubMed]
- Séguier, D.; Adams, E.S.; Kotamarti, S.; D’Anniballe, V.; Michael, Z.D.; Deivasigamani, S.; Olivier, J.; Villers, A.; Hoimes, C.; Polascik, T.J. Intratumoural immunotherapy plus focal thermal ablation for localized prostate cancer. Nat. Rev. Urol. 2024, 21, 290–302. [Google Scholar] [CrossRef]
- DiNatale, A.; Worrede, A.; Iqbal, W.; Marchioli, M.; Toth, A.; Sjöström, M.; Zhu, X.; Corey, E.; Feng, F.Y.; Zhou, W.; et al. IL-1β expression driven by androgen receptor absence or inactivation promotes prostate cancer bone metastasis. Cancer Res. Commun. 2022, 2, 1545–1557. [Google Scholar] [CrossRef]
- Dahl-Wilkie, H.; Gomez, J.; Kelley, A.; Manjit, K.; Mansoor, B.; Kanumuri, P.; Pardo, S.; Molleur, D.; Falah, R.; Konakalla, A.R.; et al. Chronic IL-1-Exposed LNCaP Cells Evolve High Basal p62-KEAP1 Complex Accumulation and NRF2/KEAP1-Dependent and -Independent Hypersensitive Nutrient Deprivation Response. Cells 2025, 14, 192. [Google Scholar] [CrossRef]
- Mao, K.F.; Sun, J.; Sun, C.; Sun, B.B.; Wu, Z.G.; Cai, J.; Zhou, C.F. Pre-treatment cytokines plus TPSA predict biochemical progression-free survival in prostate cancer metastasis and discriminate metastatic status: A retrospective study. Front. Immunol. 2025, 16, 1686570. [Google Scholar] [CrossRef]
- Chen, R.; Liu, L.; Chen, H.; Xing, C.; Zhang, T.; Pang, Y.; Yang, X. Evaluation of the clinical application value of cytokine expression profiles in the differential diagnosis of prostate cancer. Cancer Immunol. Immunother. 2024, 73, 139. [Google Scholar] [CrossRef]
- Si, T.; Guo, Z.; Hao, X. Immunologic response to primary cryoablation of high-risk prostate cancer. Cryobiology 2008, 57, 66–71. [Google Scholar] [CrossRef]
- Jorgovanovic, D.; Song, M.; Wang, L.; Zhang, Y. Roles of IFN-γ in tumor progression and regression: A review. Biomark. Res. 2020, 8, 49. [Google Scholar] [CrossRef]
- Cerqueira, M.A.; Ferrari, K.L.; de Mattos, A.C.; Monti, C.R.; Reis, L.O. T cells CD4+/CD8+ local immune modulation by prostate cancer hemi-cryoablation. World J. Urol. 2020, 38, 673–680. [Google Scholar] [CrossRef]
- Wang, A.S.; Chen, C.H.; Chou, Y.T.; Pu, Y.S. Perioperative changes in TGF-β1 levels predict the oncological outcome of cryoablation-receiving patients with localized prostate cancer. Cryobiology 2016, 73, 63–68. [Google Scholar] [CrossRef]
- Cheema, A.K.; Li, Y.; Ventimiglia, M.; Kowalczyk, K.; Hankins, R.; Bandi, G.; Janowski, E.M.; Grindrod, S.; Villagra, A.; Dritschilo, A. Radiotherapy Induces Innate Immune Responses in Patients Treated for Prostate Cancers. Clin. Cancer Res. 2023, 29, 921–929. [Google Scholar] [CrossRef]
- Si, T.G.; Wang, J.P.; Guo, Z. Analysis of circulating regulatory T cells (CD4+CD25+CD127−) after cryosurgery in prostate cancer. Asian J. Androl. 2013, 15, 461–465. [Google Scholar] [CrossRef]
- King, A.; Balaji, S.; Le, L.D.; Crombleholme, T.M.; Keswani, S.G. Regenerative Wound Healing: The Role of Interleukin-10. Adv. Wound Care 2014, 3, 315–323. [Google Scholar] [CrossRef] [PubMed]
- Chen, Z.; Meng, L.; Zhang, J.; Zhang, X. Progress in the cryoablation and cryoimmunotherapy for tumor. Front. Immunol. 2023, 14, 1094009. [Google Scholar] [CrossRef] [PubMed]
- Katongole, P.; Sande, O.J.; Nabweyambo, S.; Joloba, M.; Kajumbula, H.; Kalungi, S.; Reynolds, S.J.; Ssebambulidde, K.; Atuheirwe, M.; Orem, J.; et al. IL-6 and IL-8 cytokines are associated with elevated prostate-specific antigen levels among patients with adenocarcinoma of the prostate at the Uganda Cancer Institute. Future Oncol. 2022, 18, 661–667. [Google Scholar] [CrossRef] [PubMed]
- Tong, Y.; Cao, Y.; Jin, T.; Huang, Z.; He, Q.; Mao, M. Role of Interleukin-1 family in bone metastasis of prostate cancer. Front. Oncol. 2022, 12, 951167. [Google Scholar] [CrossRef] [PubMed]
- Sugama, K.; Suzuki, K.; Yoshitani, K.; Shiraishi, K.; Kometani, T. Urinary excretion of cytokines versus their plasma levels after endurance exercise. Exerc. Immunol. Rev. 2013, 19, 29–48. [Google Scholar] [PubMed]
- Vargová, D.; Dargaj, J.; Dohál, M.; Fraňová, S.; Ľupták, J.; Škorňová, I.; Švihra, J.; Briš, L.; Slávik, P.; Šutovská, M. Immune analysis of urine and plasma samples from patients with clear cell renal cell carcinoma. Oncol. Lett. 2024, 27, 281. [Google Scholar] [CrossRef]
- Nobles, C.; Bertone-Johnson, E.R.; Ronnenberg, A.G.; Faraj, J.M.; Zagarins, S.; Takashima-Uebelhoer, B.B.; Whitcomb, B.W. Correlation of urine and plasma cytokine levels among reproductive-aged women. Eur. J. Clin. Investig. 2015, 45, 460–465. [Google Scholar] [CrossRef] [PubMed]
- Fujita, K.; Nonomura, N. Urinary biomarkers of prostate cancer. Int. J. Urol. 2018, 25, 770–779. [Google Scholar] [CrossRef]
- Banzola, I.; Mengus, C.; Wyler, S.; Hudolin, T.; Manzella, G.; Chiarugi, A.; Boldorini, R.; Sais, G.; Schmidli, T.S.; Chiffi, G.; et al. Expression of Indoleamine 2,3-Dioxygenase Induced by IFN-γ and TNF-α as Potential Biomarker of Prostate Cancer Progression. Front. Immunol. 2018, 9, 1051. [Google Scholar] [CrossRef]
- Crocetto, F.; Musone, M.; Chianese, S.; Conforti, P.; Digitale Selvaggio, G.; Caputo, V.F.; Falabella, R.; Del Giudice, F.; Giulioni, C.; Cafarelli, A.; et al. Blood and urine-based biomarkers in prostate cancer: Current advances, clinical applications, and future directions. J. Liq. Biopsy 2025, 9, 100305. [Google Scholar] [CrossRef]
- Li, X.; Shao, M.; Zeng, X.; Qian, P.; Huang, H. Signaling pathways in the regulation of cytokine release syndrome in human diseases and intervention therapy. Signal Transduct. Target. Ther. 2021, 6, 367. [Google Scholar] [CrossRef]
- Fessé, P.; Svensson, P.A.; Zackrisson, B.; Valdman, A.; Fransson, P.; Grankvist, K.; Kristensen, I.; Langegård, U.; Ohlsson-Nevo, E.; Sjövall, K.; et al. Association of Circulating Inflammatory Biomarker Levels and Toxicity in Patients Undergoing Pelvic Radiation for Cancer: A Critical Review. Adv. Radiat. Oncol. 2025, 10, 101766. [Google Scholar] [CrossRef]
- Christensen, E.; Pintilie, M.; Evans, K.R.; Lenarduzzi, M.; Ménard, C.; Catton, C.N.; Diamandis, E.P.; Bristow, R.G. Longitudinal cytokine expression during IMRT for prostate cancer and acute treatment toxicity. Clin. Cancer Res. 2009, 15, 5576–5583. [Google Scholar] [CrossRef]
- Rosa, E.; Niccolini, B.; Di Santo, R.; Fionda, B.; Vaccaro, M.; Placidi, E.; Tabolacci, E.; De Spirito, M.; Mangoni, M.; Tagliaferri, L.; et al. A gap analysis integrating In Vitro—Research in HDR interventional radiotherapy (Modern Brachytherapy): Challenges, limitations, and future directions. Appl. Radiat. Isot. 2026, 227, 112284. [Google Scholar] [CrossRef] [PubMed]




| Cknife (n = 11) | Cryo (n = 32) | Prost (n = 10) | Overall (n = 53) | |
|---|---|---|---|---|
| Age at Treatment (years) | ||||
| Mean (SD) | 69.1 (5.79) | 68.8 (7.44) | 60.8 (6.47) | 67.3 (7.54) |
| Median [Min, Max] | 67.9 [61.2, 78.9] | 69.3 [52.1, 80.2] | 62.4 [50.2, 68.81] | 67.8 [50.2, 80.2] |
| Race | ||||
| Black | 0 (0%) | 1 (3.1%) | 3 (30.0%) | 4 (7.5%) |
| Hispanic | 0 (0%) | 0 (0%) | 1 (10.1%) | 1 (1.9%) |
| White | 3 (27.3%) | 29 (90.6%) | 6 (60.0%) | 38 (71.7%) |
| White/Hispanic | 0 (0%) | 1 (3.1%) | 0 (0%) | 1 (1.9%) |
| Unknown | 8 (72.7%) | 1 (3.1%) | 0 (0%) | 9 (17.0%) |
| Pre-trial PSA levels (ng/mL) | ||||
| Mean (SD) | NA (NA) | 6.32 (3.66) | 6.94 (3.93) | 6.55 (3.69) |
| Median [Min, Max] | NA [NA, NA] | 5.31 [1.03, 14.7] | 5.00 [4.00, 13.9] | 5.16 [1.03, 14.7] |
| Missing | 11 (100%) | 17 (53.1%) | 1 (10.0%) | 29 (54.7%) |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2026 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.
Share and Cite
Katz, A.E.; Johnson, M.; Kasselman, L.J.; Ahmed, S.; Srivastava, A.; Grossfeld, D.J.; Renna, H.A.; Li, K.; Reiss, A.B. Differential Cytokine Profiles in Prostate Cancer Under Treatment: Implications for Prognosis and Synergistic Therapy Design. Cancers 2026, 18, 967. https://doi.org/10.3390/cancers18060967
Katz AE, Johnson M, Kasselman LJ, Ahmed S, Srivastava A, Grossfeld DJ, Renna HA, Li K, Reiss AB. Differential Cytokine Profiles in Prostate Cancer Under Treatment: Implications for Prognosis and Synergistic Therapy Design. Cancers. 2026; 18(6):967. https://doi.org/10.3390/cancers18060967
Chicago/Turabian StyleKatz, Aaron E., Maryann Johnson, Lora J. Kasselman, Saba Ahmed, Ankita Srivastava, David J. Grossfeld, Heather A. Renna, Kathleen Li, and Allison B. Reiss. 2026. "Differential Cytokine Profiles in Prostate Cancer Under Treatment: Implications for Prognosis and Synergistic Therapy Design" Cancers 18, no. 6: 967. https://doi.org/10.3390/cancers18060967
APA StyleKatz, A. E., Johnson, M., Kasselman, L. J., Ahmed, S., Srivastava, A., Grossfeld, D. J., Renna, H. A., Li, K., & Reiss, A. B. (2026). Differential Cytokine Profiles in Prostate Cancer Under Treatment: Implications for Prognosis and Synergistic Therapy Design. Cancers, 18(6), 967. https://doi.org/10.3390/cancers18060967

