NK Cell Therapy in Renal Cancer Treatment

Renal cancer, a human disease originating from malignant tumors in the epithelial cells of the urinary tract, develops relatively rapidly and can occur anywhere in the kidney. Accounting for 1-2% of all adult cancers, renal cancer can affect individuals of any age, with renal cell carcinoma (RCC) representing about 3% of all cancers and comprising over 90% of malignant kidney tumors [1, 2]. Clinical symptoms of renal cancer often lack clarity. It begins when healthy cells in one or both kidneys undergo uncontrolled changes and growth, forming a mass called a renal cortical tumor. Such tumors can be malignant or benign. A malignant tumor, known as cancer, has the potential to spread to other parts of the body, while a benign tumor can grow but does not spread extensively [3].

In the United States, an estimated 81,800 adults (52,360 males and 29,440 females) received a diagnosis of renal cancer in 2023. Globally, medical professionals diagnosed approximately 431,288 cases of renal cancer in 2020. Thus, researching methods to treat renal cancer is crucial. Meanwhile, researchers have studied Natural Killer (NK) cells for their significant role in treating various cancers, including renal cell carcinoma (RCC) [4]. Hence, this report will elaborate on the advantages of applying NK cells in human renal cancer treatment.

NK Cell Therapy

Definition and Mechanism of NK Cells

Natural Killer (NK) cells are large granular lymphocytes that induce cell toxicity, capable of eliminating tumor cells without causing hypersensitivity [5]. Initially known for their ability to kill cancer cells through the extracellular mechanism of toxic granules containing perforin and granzyme, NK cells differ from CD8+ T cells in that they can directly cause cell death without prior response [6]. While NK cells are recognized for their defense against viral infections and surveillance against tumors, they are also esteemed for contributing to the generation of T helper type 1 (Th1) immunity, enhancing self-reactivity regulation and immune responses. Their cytotoxicity and production of cytokines and chemokines play pivotal roles [7].

NK cells primarily induce cell death through two different mechanisms. The most studied pathway involves granule exocytosis, where they release toxic granules containing perforin molecules that create pores and enzymes, causing cell death [8]. Another pathway involves NK cells targeting receptor-mediated cell killing. Instead of inducing the release of toxic granules, this pathway triggers a process leading to cell death by activating caspases in target cells, initiating cell death signaling through intermediary receptor control of the NK cell degranulation process  [9].

Advantages and Disadvantages of Using NK Cells in Cancer Treatment

Advantages

This method is incredibly safe and does not cause harm to the body. It does not affect or damage healthy cells. Utilizing the body’s immune system to naturally eliminate cancer cells, it aids in metastasis prevention, cancer prophylaxis, and tumor formation prevention. Moreover, immune therapy significantly impacts the immune system, protecting the body from harmful factors and enhancing overall health, reducing susceptibility to bacterial and fungal infections [10].

Disadvantages

The usage of NK cells is highly personalized due to different cancer antigen presentations in individuals, leading to varied treatment responses. Researchers need to individualize immune therapy efforts to broaden its application. Additionally, immune cells used in this therapy are artificial and might be perceived as foreign entities, potentially causing self-reactions when introduced into the body [10].

Application of NK Cells in Renal Cancer Treatment

IL-2’s Role in Eliminating Cancer Cells

IL-2, a cytokine produced by CD8 cells and NK cells, stimulates cells expressing high-affinity IL-2 receptors containing the α-, β-, and γ-chains or low-affinity dimeric receptors with only β- and γ-chains. IL-2 plays a crucial role in maintaining CD4+ and T-regulatory cells and contributes to the differentiation of CD4+ T cells into various subsets with diverse T cell functions. In January 1994, a 56-year-old man with metastatic renal cell carcinoma to the liver and lymph nodes under the carina was treated with high-dose IL-2, resulting in complete recovery from all diseases without any recurrence after 20 years [11]. Furthermore, IL-15, a cytokine produced by CD8 cells, utilizes the α-chain receptor specific to the cytokine IL-15Rα (CD215). IL-15 stimulates T cell proliferation, leading to the formation of cytotoxic lymphocytes (CTLs) and prolonged expansion of natural killer cells  [12]. Four patients with metastatic malignancy or renal cell carcinoma were infused with IL-15 into the lymphocyte compartment in the blood, initiating immediately after the first infusion. A rapid decrease in the current lymphocyte cluster could be observed within 20 minutes after IL-15 infusion for all four sampled patients. The most significant and rapid decline was observed in NK cells and CD8 cells. NK cell aggregates or flows could be observed as early as 10 minutes post-infusion, nearly absent within 30 minutes [13].

NK Cells in Controlling Metastatic Cancer

High NK cell density correlates with improved survival in renal cancer. Immune cell density significantly correlates with survival from primary to relapse in the same patient. 52 lung cancer patients with metastases originating from renal cell carcinoma from 1992 to 2010 were studied. Among them, 51 underwent unilateral nephrectomy, and one underwent partial nephrectomy. Patients with high infiltration of CD8+ T cells or DC-LAMP cells showed reduced survival rates. These immune profiles, particularly high CD8/DC-LAMP, strongly indicated worse outcomes. High NKp46+ cell density correlated with enhanced survival. The separate analysis of CD8+ and NKp46+ immune infiltration in the tumor core and invasive margin revealed prognostic significance. Cox proportional hazards modeling identified immune (CD8+/DC-LAMP+), NKp46+ cell density, metastasis at presentation, and disease-free interval as sole prognostic factors for patient survival. The study also suggested associations between pigment invasion and mediastinal lymph nodes with survival  [14].

Exosomes Enhance the Expression of NK Cells in Renal Cancer Patients

In the study conducted by Xia and colleagues, the precise role of exosomes derived from renal cell carcinoma patients in the functions of NK cells was examined (Figure 1). When there is a deficiency of NK cells, tumor size progresses more rapidly in patients. Therefore, controlling the expression of NK cells could potentially limit tumor cell development in patients. Exosomes originating from the tumor mass (Texs) act as regulators of NK cell immune responses. The results indicate that the increased levels of two cytokines, TGF-β1 and IL-10, within the exosomes are primary immune-inhibitory factors causing the lack of NK cell activation. In the study, Tex-containing TGF-β1 contributed to activating the TGF-β/Smad signaling pathway. These findings suggest that exosomes released by cancer cells promote NK cell dysfunction, aiding in reducing the duration of renal cancer treatment  [15].

Figure 1: Exosome Activity Affecting NK Cell Function

Treating Kidney Cancer by Direct Infusion of NK Cells

A substantial amount of clinically enhanced NK cells, co-cultivated with red blood cells and targeting renal cell carcinoma tissue, has been clinically tested for high efficacy in treating kidney cancer. Enriched from PBMC through immune methods, NK cells contain 1-30% mononuclear leukocytes, <1% CD3+ T cells, and 70 – 92% CD54+/CD3- NK cells. These NK cells, evaluated after 1022 days of enrichment, exhibited CD56+ CD16+ and CD56+ CD16- expressions of 84.3% and 14.7%, respectively. A simultaneous treatment involving the expansion of NK cells by direct infusion and conventional bortezomib treatment was performed on renal cell carcinoma (RCC) patients. Results obtained after 1218 days revealed that newly infused NK cells destroyed around 28% to 56% of renal cell carcinoma cells, significantly higher than the corresponding bortezomib treatment [16].

Further clinical research is necessary to evaluate the practical efficacy of NK cell therapy in treating and supporting kidney cancer patients. However, current studies also offer considerable hope for those with kidney cancer, providing additional options in cellular therapy for this condition.

References:

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