Lung cancer is a leading cause of death worldwide. Natural killer cells play a critical role in immunotherapy for cancer patients. The natural killer or NK cells play a crucial role in cancer patients and developing an understanding of the mechanisms through which their activity is inhibited or enhanced in the case of cancer patients, shall contribute a great deal in finding the most suitable and effective treatment of cancer patients and also enhance their life. The present research paper is restricted to the study of cell mechanisms involving NK cells and their inhibitor and activators in the case of patients in lung cancer. The research may also be used for the study of similar mechanisms in patients with other cancer types.
The cancer tumor cells have a great negative impact on the normal functioning of the natural killer cells through the molecular cell mechanisms in the tumor microenvironment . The present research paper aims to understand the mechanism involved in the impairment of natural killer cells for cancer patients that affects their treatment plans through immunotherapy.
Significance of Research
The significance of the current research study lies in the fact that the developing an understanding about the factors and mechanism through which the tumor cells impair the normal functioning of the natural killer (NK cells) cells shall help the therapists in devising mechanisms to counter this effect and thus help to improve the treatment plans for cancer patients.
The research methodology used in the current research is the analysis of the secondary data through research papers that involve the description and reports of research studies by other science scholars on the similar topics. The secondary research has many benefits. It is a cost-effective and less time consuming method of research and allows the research study to be compaleted in a shorter time span.
Natural killer cells are large granular lymphocytes are independent and non-specific immune cells . These cells do not have any MHC restriction to target cell recognition or destruction and have the capability to directly kill the tumor cells and virus infected cells without being pre-sensitized .
Natural killer cells (NK cells) are involved in the lysis of the tumor cells as the pathogen infected cells. The activity of the NK cells is regulated by the functionally opposing and inhibitory receptors that bind class 1 MHC molecules and activating receptors that bind the ligands on the tumors or the virus infected cells .
In a resting state the functions of the activating receptors is inhibited due to the fact that inhibitory receptors are ligated with the class 1 MHC molecules. The loss of MHC class 1 molecules due to an infection or tumor formation relieves this inhibition and thus facilitates the NK activation . In the case of humans, the inhibitory receptors include killer Ig-like receptor 2DL, killer Ig-like receptor 3DL1, and CD94/NKG2A and the activating receptors include NKp30, NKp44, NKp46 and NKG2D . NKG2D is expressed in the case of NK cells, CD8 αβ T cells, and γδ T cells . NKG2D is thought to play a critical role in the regulation of the tumor development and growth in cancer patients . Also, it is important to know that the ligands of NK2GD are not found in normal cells and they are formed only in tumor patients or in cases of stress or infection. This is an important criteria that forms the basis of the scientific study for cancer patients.
TGF -β1 is a potential immune suppressing molecule that is produced by many cancer cells. The molecule has been known to stimulate the growth of tumors by inhibiting the functionality of the NK cells by reducing them toxicity, expansion and cytokine production in cancer patients. TGF-β1 is thought to interfere with the functioning of the NK cells by downgrading of the expression of the NKG2D.
The use of targeted cell agents in cancer therapy has been quite successful. EGFR is frequently over-expressed in the case of non-small cell lung cancers . As an inhibitor of EGFR, gefitinib is an excellent treatment option as it can induce clinical responses and improve the survival of cancer patients through inhibition of EGFR based signals and proliferation of tumor cells . Several factors affect the response of the cancer patients towards the immunotherapy treatments and in some cases, the patients may develop an immunity towards the gefitinib action thus affecting their treatment plans.
Observations and Discussion
In a research study by , it was found that TGF-β1 that is secreted by the tumors may be responsible for the poor ability of the NK cells to conduct lysis through the down regulation of an NK activating receptor NKG2D. It has been found that the plasma concentration of TGF-β1 is much higher in the case of cancer patients in comparsion to the normal individuals and this elevation is thought to be inversely correlated with the surface expression of NKG2D on the NK cells of the cancer patients. Also, the incubation of the NK cells with the plasma that was obtained from the cancer patients specifically down-modulated the surface NKG2D expression and the addition of the neutralizing anti-TGF-β1 mAbs was successful in completely restoring the surface NKG2D expression. Similarly the inclubation of the NK cells and the lymphokine activated killer cells with TGF-β1 resulted in a tremendous decrease in the activity of the NKG2D expression being associated with the impaired NK cells cytotoxicity. Also, the modulation of the NKG2D by anti-TGF-β1 is found to be specific in nature as the expresson of the other NK receptors remained unaffected by anti-TGF-β1 . The impaired toxicity by the anti-TGF-β1 was not due to the alteration by the lytic molecules such as perforin or Fas but due to the lack of the expression of NKG2D. The research study therefore suggests that impaired function of natural killer cells in the cancer patients is due to the down modulation by the activating receptors such as NKG2D via anti-TGF-β1 secretion .
In another research study that was conducted by , it was found that the infiltration of the NK cells in tumor periphery was related with the prognosis of the lung cancer patients. The number of NK cells that infiltrated in the lung cancer tissue depends on many factors such as the type of pathology, the size of the primary cancer, the history of smoking and the prognosis of cancer patients . The expression of the NK cells inhibitor receptors was found to increase substantially in the tumor micro-environment and the expression of the NK cells activated receptors decreased to a great level .
The research study by studied the impact of gefitinib on the interaction between the NK cells and the lung cancer cells. It was found that gefitinib increased the cytotoxicity of the NK cells towards the human lung cancer (H1975 cells with EGFR L858R + T790M mutations) but not in the case of A549 cells with wild type EGFR . Gefitinib was successful in blocking the immune system by up regulating the expression of the NKG2D ligands and the expression of NKG2D on NK cells. NKG2D antibody are found to block the enhanced NK cytotoxicity by gefitinib . Gefitinib is found to increase autophagy and MPR expression in the case of H1975 cells that further enhance the sensitivity to NK cells based immunotherapy in cancer patients.
The survival rate of the cancer patients is highly dependent on the degree of the NK cell infiltration in lung cancer. The down regulation of NKG2D, Ly49I and the up regulation of NKG2A is an indication of the immune tolerance mechanism also facilitates the metastasis in the tumor environment for cancer patients . Gefitinib is found to greatly enhance the NK cell toxicity to lung cancer cells with EGFR L858R + T790M resistance mutation and therefore a combination of EGFR tyrokinase inhibitors and NK cells based immunotherapy may be a suitable strategy for treatment of patients with non-small lung cancer . The results of the current study shall help in devising the future treatments for cancer patients and in particular lung cancer patients using the technique of immunotherapy.
He, S., Yin, T., Li, D., Gao, X., Wan, Y., Ma, X., . . . Wang, Y. (2013). Enhanced interaction between natural killer cells and lung cancer cells: involvement in gefitinib-mediated immunoregulation. Journal of Translational Medicine.
Jin, S., Deng, Y., Hao, J.-W., Li, Y., Liu, B., Yu, Y., . . . Zhou, Q.-H. (2014). NK Cell Phenotypic Modulation in Lung Cancer Environment. PLOS.
Lee, J.-C., Lee, K.-M., Kim, D.-W., & Heo, D. S. (2004). Elevated TGF-β1 Secretion and Down-Modulation of NKG2D Underlies Impaired NK Cytotoxicity in Cancer Patients. The Journal of Immunology, 7335-7340.