Natural Killer Cell (NK) Therapy in Lung Cancer Treatment

Cancer remains one of the leading causes of illness and death worldwide, with approximately 238,340 recent cases of lung cancer reported (117,550 in males and 120,790 in females). According to the American Cancer Society, the American Cancer Society attributes around 127,070 deaths to lung cancer (67,160 in males and 59,910 in females) [1]. Lung cancer primarily affects older individuals, with most diagnoses occurring in individuals aged 65 and older and a small number diagnosed before the age of 45. The prognosis for lung cancer depends on the stage and histological classification of the tumor, as well as clinical factors. Only about 18.1% of lung cancer patients survive five years after diagnosis [1, 2]. Recently, researchers have been studying the interaction between the immune system and lung cancer to explore new treatment strategies, such as immune therapy. Increasing understanding of immune mechanisms in lung cancer demonstrates complex immune interactions at different stages of the disease. One crucial immune cell in the tumor microenvironment is the Natural Killer (NK) cells, which may play a significant role in cancer treatment [3].

Characteristics of the Lungs and NK Cells in the Lungs

The lungs encounter approximately 10,000 liters of inhaled air daily containing countless disease-causing agents. This constant exposure requires a finely tuned immune system to sense and protect the host rapidly in this vital contact area [4]. Consequently, the airways have a vast arsenal of host defense mechanisms, mostly immune-related. Complex interactions between resident immune cells and invading cells coordinated with secreted proteins such as defensins, mucins, or Collectins form the outcome of pathogen-host-allergic interactions in the respiratory microenvironment [4]. Lungs, constantly exposed to environmental and self-stimuli, are sites with a high incidence of primary tumors and metastases. Most lung cancer statistics include both Small Cell Lung Cancer (SCLC) and Non-Small Cell Lung Cancer (NSCLC). Generally, about 10% to 15% of all lung cancers are SCLC, and around 80% to 85% are NSCLC  [5].

Rapid and effective immune responses in the lungs to prevent tumor formation and invasion without leading to excessive inflammation are necessary to maintain balance in the lungs. As a type of innate immune cell, NK cells are considered the host’s first line of defense against tumors and viruses [6]. Additionally, studies have observed the role of NK cells in various lung diseases, such as lung cancer, chronic obstructive pulmonary disease (COPD), asthma, as well as infections [7, 8]. NK cells are present at high frequencies in peripheral blood, lymph nodes, the spleen, and bone marrow, and they can migrate to infected sites in the body [6]. NK cells are crucial in both innate and adaptive immune systems. They activate mononuclear cells and cytotoxic T cells. CD16 and CD56 markers help identify NK cell subsets. In humans, NK cells are divided into two main subsets with different functions and maturity states: CD56-bright and CD56-dim  [7]. Additionally, cytokines such as interleukin (IL)-12, IL-15, IL-18, interferon (IFN), tumor necrosis factor-alpha (TNF-α), as well as Toll-like receptors (TLR), are potent activators of NK cell functions [8]. These two NK cell groups have different cytotoxicity levels and produce different cytokines. IFN-γ maintains anti-tumor activity by activating T cells to destroy tumor cells. TNF-α can have direct cytotoxic activity by inducing programmed cell death via Caspase intermediates.

NK Cells in Lung Cancer

NK cells produce cell-killing enzymes and cytokines, including granzyme, perforin, and IFN-γ, necessary for suppressing the growth of lung cancer cells [8]. Normally, tumor cells release immune-suppressive cytokines like IL-10 or TGF-β, which inhibit NK cell function [9, 10]. The expression of TGF-β1 protein in NSCLC tissue is significantly higher than in normal lung tissue. In NSCLC tissue, the production of IL-10 is also increased, and reduced survival rates are associated with higher levels of serum IL-10. Studies have reported an increased Treg ratio and decreased NK cell ratio in tumor tissues in lung cancer, which is associated with IL-10 primarily produced by regulatory T cells (Treg) [11]. Specific molecules expressed in NK cells may play a crucial role in treating malignant tumors, including lung cancer. Studies highlight the role and significance of NK cells in lung cancer development and the impact of NK cells on prognosis and survival after contracting this disease. The survival of lung cancer patients correlates positively with NK cell infiltration in lung cancer [11]. Another study primarily observed CD56-bright cells in tumor infiltration. The cytotoxic ability of these cells isolated from lower-grade cancer tissues was lower compared to NK cells from peripheral blood or normal lung tissues.

NK Cell-Based Immunotherapy in Lung Cancer

There is increasing evidence that NK cells can selectively recognize and eliminate cancer cells. Some studies indicate the fundamental role of NK cells in preventing lung metastasis [7, 9, 12]. Additionally, the activation of NK cells through IL-12 may enhance the cytolytic activity of lung cancer cells [13]. In a mouse lung cancer model, immune therapy using NK cells has shown effectiveness in treating lung cancer. NK cell efficacy is also reflected in their ability to cause cell toxicity in NSCLC patients  [9, 10]. Overall survival has been demonstrated to improve in patients treated with NK cell-based immune therapy. In a recent study, clinical outcomes of surgery combined with allogeneic NK cell immunotherapy for advanced NSCLC were improved with enhanced immune functions and quality of life [14]. Furthermore, a randomized controlled trial in phase II is currently underway to test the efficacy of targeted NK cell-nourishing immunotherapy for 90 stage III NSCLC patients after chemotherapy and radiotherapy (NCT02118415) [15]. Researchers have also tested the effectiveness of targeted NK cell-nourishing immune therapy in SCLC patients, which prolonged the survival of 29 patients [16].

So, NK cells have been demonstrated to play a crucial role in controlling effective immune responses against lung cancer. NK cells can eliminate cancer cells through direct cytotoxicity, inducing programmed cell death, or secreting IFN-γ. Most studies investigating NK cells in animal models of cancer conclude that NK cells may act as anti-tumor agents in lung cancer. Many clinical studies focus on the role of NK cells in the process of lung cancer development to facilitate the development of new NK cell-based lung cancer treatment methods. Immunological studies utilizing NK cell-based approaches may change the structure and principles of lung cancer treatment in the future. Further analysis of post-lung transplant lung and/or graft tissue compared to the host’s lung post-bone marrow transplant will enhance our understanding of NK cell entities in the lungs. With deeper knowledge of the biology of lung NK cells, anticipated effective treatment strategies based on NK cells will likely be applied to treat lung-related diseases.

References:

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