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INVITED COMMENTARY
Year : 2022  |  Volume : 24  |  Issue : 2  |  Page : 223-224

Impact of IL-23 in prostate cancer


Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, 450 West Drive, Chapel Hill, NC 27599, USA

Date of Submission10-Oct-2021
Date of Acceptance20-Oct-2021
Date of Web Publication26-Nov-2021

Correspondence Address:
Bhalchandra Mirlekar
Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, 450 West Drive, Chapel Hill, NC 27599
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/aja2021100

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How to cite this article:
Mirlekar B. Impact of IL-23 in prostate cancer. Asian J Androl 2022;24:223-4

How to cite this URL:
Mirlekar B. Impact of IL-23 in prostate cancer. Asian J Androl [serial online] 2022 [cited 2022 Aug 18];24:223-4. Available from: https://www.ajandrology.com/text.asp?2022/24/2/223/331249

Cytokines play an essential role in governing the overall immune response toward cancer. Recently, the role of IL-12 family cytokines in dictating immune response toward cancer has been well appreciated.[1] IL-23 is one of such heterodimeric cytokines belonging to the IL-12 family cytokine, composed of p19 and p40 subunits.[2] The role of IL-23 in regulating tumorigenesis is controversial. In some cancer settings, IL-23 activates the effector immune system and has antitumorigenic functions; on the other hand, it can support immune regulatory response and favor tumor growth.[3] In this issue of Asian Journal of Andrology, Liu et al.[4] reported the novel functions of IL-23, a cytokine that regulates both innate and adaptive immune cells; especially, it is well known to maintain Th17 cell phenotype in prostate cancer. Prostate cancer is one of the utmost challenging tumor types and is the most common cancer in men, and one man in eight will be diagnosed with prostate cancer.[5],[6]

To date, prostate cancer can be diagnosed using prostate-specific antigen (PSA) testing in blood or with a digital rectal examination (DRE). Nevertheless, both tests are imperfect and sometimes give false-positive results even in the absence of cancer and vice versa.[7],[8],[9] It might lead to prostate surgeries even men do not have cancer, and false-negative tests can go without specific treatment even they have cancer. It demonstrates the urgent need for a different diagnostic approach for patients with prostate cancer. Recent research studies show that certain cytokine levels and prostate tumorigenesis go hand in hand and promote cancer, from low-grade prostatic intraepithelial neoplasia (PIN) to high-grade PIN, and even potentiates metastasis outgrowth of the tumor.[10],[11],[12] Infiltration of regulatory immune cells is essential in regulating prostate cancer growth and metastasis. Recent studies focused on delineating the functions of regulatory cells in directly initiating and maintaining prostate cancer progression. Several pro-inflammatory cytokines have been shown to control prostate cancer growth; mainly, IL-17–producing Th17 cells have been shown to promote prostate cancer by modulating response in a mouse model of prostate cancer.[13],[14] Thus, the interplay between immune regulatory cells, cytokine signaling and initiation, and maintenance of prostate cancer growth has emerged as a crucial node in regulating prostate tumorigenesis.

Liu et al.[4] revealed the essential aspect of IL-23, a cytokine involved in the expansion of Th17 cells and responsible for several autoimmune and inflammatory diseases, as a prognostic factor in patients with metastatic prostate cancer. Authors showed that IL-23–positive cells were correlated with disease progression and abundantly present within prostate cancer tissue. To delineate the diagnostic potential of IL-23, the authors evaluated IL-23 expression in the TCGA-PRAD cohort and observed that it is positively correlated with the pT stage and the Gleason score. The IL-23 expression is directly related to poor survival and castration-resistant prostate cancer (CRPC)-free survival. These observations are crucial because they show the importance of proinflammatory cytokine IL-23 in the diagnosis of prostate cancer and correlate with the patient's survival. Interestingly, the authors also indicated that IL-23–secreting cells or its expression status is different in the advanced stage of the disease. In addition, using immunohistochemical analysis, authors confirmed the presence of IL-23+ cells in prostate cancer tissues, and the prostate cancer patients with higher Gleason scores have enhanced IL-23+ cells accumulation compared to low Gleason scores.[4]

The authors further showed that metastasis cancer lesions had increased IL-23+ cells than those of nonmetastasized lesions. Patients with increased IL-23+ cells infiltration have poor clinical outcomes than patients with fewer IL-23+ cells infiltrated the group. These are essential findings and undoubtedly valuable for the clinical setting, where they can help design strategies for the cancer patient's treatment and guide the therapy [Figure 1]. The authors further showed that the increased IL-23+ cell infiltration is associated with a higher risk of death and CRPC grade. In addition, the authors presented the Gleason score and nerve invasion that showed the increased risk in CRPC-free survival models and revealed that IL-23+ cells can self-sufficiently anticipate the prognosis of metastatic prostate cancer patients. Interestingly, the authors found that IL-23+ cells predict poor clinical outcomes in the patients who received the abiraterone treatment. Inversely, it is not found in patients who received the docetaxel treatment.[4]
Figure 1: Higher IL-23+ cells infiltration can be a good prognostic indicator in prostate cancer.

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Although this and few other reports analyzed the role of IL-23 in cancer initiation and metastasis and provided an important aspect into its role from diagnosis to drug discovery, several questions remain. First, how IL-23+ cells infiltrated and recruited at the tumor site and how IL-23 signaling affects the overall immune and cancer cell phenotype are not well studied. Second, it is also not well acknowledge how different stimuli or cytokines in the tumor environment affect IL-23+ cells, and what promising intracellular signaling and transcription factors govern IL-23 expression in target cells, which might lead to tumorigenesis and worse survival. Moreover, the precise function of IL-23–producing cells in the tumor microenvironment is unclear, as they stabilize the Th17 cell phenotype; however, the role of Th17 cells in tumorigenesis, especially in human prostate cancer, is controversial.[15] In conclusion, the precise signaling and critical transcription factors dictate the fate of IL-23+ cells, and target cells of IL-23 need to be evaluated. Those are crucial in prostate cancer and should be comprehensively illuminated, as these details will help design potential and novel targeted therapy for the treatment of prostate cancer.


  Competing Interests Top


The author declared no competing interests.



 
  References Top

1.
Mirlekar B, Pylayeva-Gupta Y. IL-12 family cytokines in cancer and immunotherapy. Cancers 2021; 13: 167.  Back to cited text no. 1
    
2.
Vignali DA, Kuchroo VK. IL-12 family cytokines: immunological playmakers. Nat Immunol 2012; 13: 722–8.  Back to cited text no. 2
    
3.
Yan J, Smyth MJ, Teng MW. Interleukin (IL)-12 and IL-23 and their conflicting roles in cancer. Cold Spring Harb Perspect Biol 2018; 10: a028530.  Back to cited text no. 3
    
4.
Liu Z, Zhang JY, Yang YJ, Chang K, Wang QF, et al. High IL-23+ cells infiltration correlates with worse clinical outcomes and abiraterone effectiveness in patients with prostate cancer. Asian J Androl 2021; Doi: 10.4103/aja202173. [Online ahead of print].  Back to cited text no. 4
    
5.
Pernar CH, Ebot EM, Wilson KM, Mucci LA. The epidemiology of prostate cancer. Cold Spring Harb Perspect Med 2018; 8: a030361.  Back to cited text no. 5
    
6.
Rawla P. Epidemiology of prostate cancer. World J Oncol 2019; 10: 63.  Back to cited text no. 6
    
7.
Bernal-Soriano MC, Parker LA, López-Garrigos M, Hernández-Aguado I, Caballero-Romeu JP, et al. Factors associated with false negative and false positive results of prostate-specific antigen (PSA) and the impact on patient health: cohort study protocol. Medicine (Baltimore) 2019; 98: e17451.  Back to cited text no. 7
    
8.
Naji L, Randhawa H, Sohani Z, Dennis B, Lautenbach D, et al. Digital rectal examination for prostate cancer screening in primary care: a systematic review and meta-analysis. Ann Fam Med 2018; 16: 149–54.  Back to cited text no. 8
    
9.
Palsdottir T, Nordstrom T, Karlsson A, Grönberg H, Clements M, et al. The impact of different prostate-specific antigen (PSA) testing intervals on Gleason score at diagnosis and the risk of experiencing false-positive biopsy recommendations: a population-based cohort study. BMJ Open 2019; 9: e027958.  Back to cited text no. 9
    
10.
Adekoya TO, Richardson RM. Cytokines and chemokines as mediators of prostate cancer metastasis. Int J Mol Sci 2020; 21: 4449.  Back to cited text no. 10
    
11.
Singh J, Sohal SS, Lim A, Duncan H, Thachil T, et al. 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.  Back to cited text no. 11
    
12.
Stanojković TP, Matić IZ, Petrović N, Stanković V, Kopčalić K, et al. Evaluation of cytokine expression and circulating immune cell subsets as potential parameters of acute radiation toxicity in prostate cancer patients. Sci Rep 2020; 10: 19002.  Back to cited text no. 12
    
13.
Duan Z, Miller HD, Fu X, Ge D, Jin B, et al. Th17 cells promote tumor growth in an immunocompetent orthotopic mouse model of prostate cancer. Am J Clin Exp Urol 2019; 7: 249–61.  Back to cited text no. 13
    
14.
Zhang Q, Liu S, Ge D, Cunningham DM, Huang F, et al. Targeting Th17-IL-17 pathway in prevention of micro-invasive prostate cancer in a mouse model. Prostate 2017; 77: 888–99.  Back to cited text no. 14
    
15.
Kuen DS, Kim BS, Chung Y. IL-17-producing cells in tumor immunity: friends or foes? Immune Netw 2020; 20: e6.  Back to cited text no. 15
    


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