The Role of Natural Killer Cells in the Management of Prostate Cancer. A Systematic Review

Review Article

Austin Oncol. 2022; 6(1): 1022.

The Role of Natural Killer Cells in the Management of Prostate Cancer. A Systematic Review

Fanijavadi S1*, Hansen TF1,2 and Zedan AH1

¹Department of Oncology, Vejle Hospital, University Hospital of Southern Denmark, Denmark

²Institute of Regional Health Research, University of Southern Denmark, Denmark

*Corresponding author: Fanijavadi S, Department of Oncology, Vejle Hospital, University Hospital of Southern Denmark, Beriderbakken 4, 7100 Vejle, Denmark; Email: [email protected]

Received: September 27, 2022; Accepted: October 27, 2022; Published: November 03, 2022


Purpose: The role of Natural Killer (NK) cells in the management of Prostate Cancer (PCa) is still not fully understood. It has been argued that measurement of NK cells in a blood sample may be used as a reliable, minimally invasive tool for PCa screening and evaluation of treatment effect and survival. The purpose of this systematic review was to search the current literature for evidence on the potential role of NK cells in the management of prostate cancer.

Patients and Methods: We reviewed the literature on NK cells in relation to PCa patients. A systematic review using Pub Med and scientific meeting records was carried out from February to May 2021 according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). A total of 32 fulltext papers were identified.

Conclusion: Current evidence supports the hypothesis that NK cell assays might become an effective tool for screening, diagnostics, staging, and prediction of outcome in patients with PCa, but further investigation is needed to elucidate the role of NK cell phenotypes. Also, prospective studies on the implementation of NK cell assays as a supplement in personalized approaches to PCa management are required.

Keywords: Natural killer cell; Prostatic neoplasm; mCRPC; Biomarker; Immunological fingerprint; Personalized medicine


Prostate Cancer

Prostate Cancer (PCa) is the second most common noncutaneous neoplasm and the 5th most common cause of cancerrelated deaths (7%) in men worldwide [1]. PCa is a heterogeneous disease with most cases progressing slowly [2].

Measurement of serum Prostate-Specific Antigen (PSA) is the cornerstone in early detection and monitoring of PCa [3]. Since its introduction in the late 1960s, PSA has dramatically shifted PCa staging, with most cases diagnosed as a prostate-confined tumor [4]. Nevertheless, there is still no consensus about the cutoff for an elevated PSA [5]. With a cutoff of four ng/ml the positive predictive value of PSA in the diagnosis of PCa varies widely from 25 to 40% [6] with a sensitivity and specificity of around 20% and 65%, respectively [7]. In the mid-1980s there was a rapid rise in the PCa incidence due to the introduction of PSA testing, but the recent implementation of more conservative PSA testing recommendations has led to a decline in the diagnosis of new cases of PCa [8].

The conventional diagnostic tool for PCa is Transrectal Ultrasound (TRUS) guided biopsy [9]. This procedure still has many clinical challenges, including being invasive, having side effects, and the risk of false-negative results [10]. Biopsy targeted by Magnetic Resonance Imaging (MRI) seems to overcome the pitfalls of TRUSguided biopsy and improves diagnostic accuracy [11].

The risk of recurrence after curatively intended management of PCa depends mainly on the disease stage at initial diagnosis. Such stratification is usually based on the clinical Tumor, Node and Metastasis stage (TNM), PSA levels, and biopsy Gleason Score (GS) [2].

Radical prostatectomy and radiotherapy are the ultimate treatments for localized and locally advanced PCa [12] while Androgen Deprivation Therapy (ADT) is a backbone in the medical treatment for both high-risk localized PCa and the metastatic setting [13]. In almost all patients with incurable PCa the disease will eventually progress to the Castration-Resistant (CRPC) stage with 35% developing metastases and ultimately dying within two to four years [14].

There is accumulating evidence that an impaired immune response is an essential factor in the pathogenesis of PCa [15]. Both preclinical and clinical studies have explored the role of inflammation in PCa development and progression. Due to the correlation between immune system activity and management of cancer, many efforts are ongoing to elucidate the impact of immune biomarkers in relation to early diagnosis and optimal treatment approaches in different cancer types, including PCa.

Natural Killer Cells

The innate and acquired immune systems protect the host from foreign pathogens by differentiating between “self” and “non-self” antigens [16]. Natural Killer (NK) cells are innate effector lymphocytes that differ from B and T cells. Among all circulating lymphocytes, 10- 15% are considered to be NK cells [17].

Human NK cells are identified by the absence of a Cluster of Differentiation 3 (CD3) and the presence of CD56. They can be subdivided into different populations based on the expression of CD16 and CD56 (CD56dimCD16+ and CD56brightCD16-) [18]. The NK cells can be broadly divided into a CD56dim cytotoxic subset, which represents the majority of NK cells in the blood, and a CD56bright cytokine producer subset [19]. Functionally, CD56bright NK cells are immature but can differentiate into CD56dim with high cytotoxic potential [16].

The effective function of NK cells depends on the balance between activating receptors such as NK cell Group 2 member D (NKG2D) and inhibitory receptors like KIR (killer cell immunoglobulin-like receptors) [19,20], following ligation with stress ligands and Major Histocompatibility Complex (MHC) class I molecules, respectively [21]. Natural Killer Cell Activity (NKA) can also be enhanced by interleukin-2(IL-2), and interferons and can be suppressed by suppressor T cells, suppressor monocytes, and prostaglandins.

Characterization of the target molecule(s) and the mechanisms by which NK cells recognize their target structure(s) are unanswered questions that have attracted considerable attention [22].

Natural Killer Cells in Cancer

The NK cells are effector cells that spontaneously lyse normal cells infected by microbial pathogens and a variety of syngeneic and allogeneic tumor cells. As part of the innate immune system, NK cells can recognize the absent or low expression of class I Human Leukocyte Antigen (HLA) molecules on target cells and lyse them directly. The NK cells can also recognize and bind to the NK recognition structure of the tumor cells, which leads to the releasing of NK Cytotoxic Factor (NKCF) and tumor cell lysis [23]. Another mechanism of NK-mediated target cell lysis is Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) through activation of the CD16 receptor [24]. NKA also depends on the recycling capacity of NK cells after lysis of the tumor cell and can be augmented by interferon [17].

NK cells play a critical role in tumor immune surveillance by cytotoxic activity, cytokine production [25], and directly inducing the death of tumor cells by secreting perforin and granzymes [26]. In addition, NK cells secrete pro-inflammatory cytokines, which leads to stimulation of the adaptive immune response to neutralize the escape mechanisms developed by tumor cells [15]. In patients with solid tumors, NKA is depressed and may be associated with aberrant immune regulation, which leads to the development of the tumor.

Major mechanisms associated with impaired NK cell functioning in cancer patients are down regulation of lytic perforin and granzyme production, accompanied by reduction of degranulation capabilities [26,27]. Down-regulation of NK cell-activating receptors and inhibition of the NK cell cytotoxic function are connected with exposure of NK cells to some immunosuppressive cytokines such as transforming growth factor-beta (TGF-β) produced by tumors [28]. Additionally, the killing capability of NK cells can be affected by inhibition of the natural cytotoxicity triggering receptor 1, which is an NK cell-specific surface molecule of the 46 kD (NCR1/NKp46) pathway.

Natural Killer Cells in Prostate Cancer

Some studies have indicated that inflammation may play a role in the pathogenesis of PCa, an important factor of which is an impaired immune response [15] with the NK cells distributed throughout the stroma and around the glandular epithelium [29].

NKA may be applied both as a supportive diagnostic marker in addition to PSA [15] and as a prognostic factor in patients with PCa [30]. Furthermore, the immune system as well as the tumor micro environment can be affected by treatments such as ADT, which increase the number of lymphocytes, including NK cells [13,31].

It has been observed that a combination of immunotherapeutic drugs such as cancer vaccines, checkpoint inhibitors, cytokines, and pharmacotherapeutic and molecular agents enhance the immune response in PCa, and therefore, some studies hypothesized that NK cells may also be used as a therapeutic tool for the management of PCa [32].

In the present review, we elucidate the potential role of NK cells in the pathogenesis, screening, diagnostics, prognostics and prediction of treatment effect in PCa patients.


This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA). The PRISMA flow chart was used to map the records identified, included and excluded, and the reasons for exclusion (Figure 1).