At OncoBites, we’ve talked about many facets of cancer, the many internal and external factors that can affect tumor growth, and the established and developing methods to detect and treat cancer. We’ve also begun to cover the many ways in which biomedical science falls short in effectively treating cancer. Being diagnosed with cancer is terrifying: cells in your body are growing out of control spitting off even more cells that can invade other issues and eventually take over your entire body. Still, some cancers like lung cancer can feel scarier than others because they spread faster or have fewer treatment options. While targeted and immunotherapies have been developed for many other cancers, chemotherapy, radiotherapy, and surgery have been the standard of care for lung cancer for decades. Only 18.1% of lung cancer patients survive for five or more years after being diagnosed.
As we’ve discussed previously on OncoBites, radiation and chemotherapies target rapidly dividing cells, with the logic that tumor cells divide more quickly than most of our own cells. However, healthy cells also suffer the consequences of these treatments, and the side effects can be quite severe and debilitating. Recent cancer research has trended towards immunotherapy, which can harness the many different cells of the immune system, the patient’s natural defense system, to attack and kill tumor cells. Morgan has already introduced us to one of the cells that make up this defense system: the Natural Killer cell.
A Natural Killer (NK) cell is a type of white blood cell. White blood cells are a part of our immune system that circulate in our blood and seek out foreign bodies like a virus-infected cell, a microorganism like a bacterium, or a tumor cell. Tumor cells have undergone changes in their DNA which lead to changes in the cell that make them be recognized as an outsider in our body. When the NK cell detects a foreign body, they poke a hole in the targeted cell and release chemicals through the hole to kill the cell. NK cells have a variety of functions working with other immune cells in our body, all with the ultimate goal of helping our body get rid of foreign invaders.
Unfortunately, NK cell function is inhibited by smoking, a major cause of lung cancer. Smoking cigarettes impairs NK cell function including detection and clearance of tumor cells. Reduced killing activity in NK cells observed in smokers reduced cellular signals required for NK cell function. A study of men who smoked for over ten years found that NK cells and immunoglobulins, an important class of immune signaling proteins, are reduced in smokers.
We know NK cells are dysfunctional in smoking which contributes to lung cancer, but how can we use that to prevent or treat lung cancer? The enzymes and proteins that NK cells make are really important to prevent lung cancer cells from replicating and multiplying, and these are reduced in lung cancer patients 1,2,3. When NK cells are present in a tumor, the tumor environment makes them less effective at killing tumor cells. When NK cells were taken from tumors and studied in the lab, they weren’t as good at killing cell as NK cells taken from healthy tissue. Patients who have more NK cells infiltrated within their lung tumors have a better chance of survival, suggesting that immune function generally and NK cell function specifically exert a major influence on patient survival.
Though the tumor environment impairs NK cells function, we can alter NK cells to overcome their environments to be better at fighting tumors. An NK cell line was derived from a patient with lymphoma and when that was infused to patients with solid tumors and sarcomas, they saw the additional NK cells helped prevent tumors in 75% of patients with lung cancer. Treating patients with IL-15, a protein required for NK cell activation, increased the number of “killer” cells. Increasing the pool of functioning NK cells in cancer patients by transferring these cells from a healthy donor increased survival.
So here is the bottom line: NK cells are important to provide protection against cancer because they are part of our bodies natural defenses against invading cells/organisms. Unfortunately, cancer creates an environment that decreases both the number and functionality of NK cells, reducing their ability to protect our body. The next steps in developing NK cell-based immunotherapies will require a more thorough understanding of how tumors decrease NK cell numbers and function. That way we can target those mechanisms to increase NK cell effectiveness in the tumor microenvironment and help patients fight off tumor cells with their own natural defense mechanisms. We already have a number of studies underway but we still have work to do before lung cancer patients can use NK based immunotherapy as one of the mainstays of treatment.
Primary work discussed:
Aktaş, O. N., Öztürk, A. B., Erman, B., Erus, S., Tanju, S., & Dilege, Ş. (2018). Role of natural killer cells in lung cancer. Journal of Cancer Research and Clinical Oncology, 144(6), 997–1003. https://doi.org/10.1007/s00432-018-2635-3
Other works discussed:
Al Omar, S. Y., Marshall, E., Middleton, D., & Christmas, S. E. (2011). Increased killer immunoglobulin-like receptor expression and functional defects in natural killer cells in lung cancer. Immunology, 133(1), 94–104. https://doi.org/10.1111/j.1365-2567.2011.03415.x
Hodge, G., Barnawi, J., Jurisevic, C., Moffat, D., Holmes, M., Reynolds, P. N., … Hodge, S. (2014). Lung cancer is associated with decreased expression of perforin, granzyme B and interferon (IFN)-γ by infiltrating lung tissue T cells, natural killer (NK) T-like and NK cells. Clinical & Experimental Immunology, 178(1), 79–85. https://doi.org/10.1111/cei.12392
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 ONE, 9(10), e109976. https://doi.org/10.1371/journal.pone.0109976
Mian, M. F., Lauzon, N. M., Stämpfli, M. R., Mossman, K. L., & Ashkar, A. A. (2008). Impairment of human NK cell cytotoxic activity and cytokine release by cigarette smoke. Journal of Leukocyte Biology, 83(3), 774–784. https://doi.org/10.1189/jlb.0707481
Miller, J. S., Morishima, C., McNeel, D. G., Patel, M. R., Kohrt, H. E. K., Thompson, J. A., … Conlon, K. C. (2018). A First-in-Human Phase I Study of Subcutaneous Outpatient Recombinant Human IL15 (rhIL15) in Adults with Advanced Solid Tumors. Clinical Cancer Research : An Official Journal of the American Association for Cancer Research, 24(7), 1525–1535. https://doi.org/10.1158/1078-0432.CCR-17-2451
Moszczyński, P., Zabiński, Z., Moszczyński, P., Rutowski, J., Słowiński, S., & Tabarowski, Z. (2001). Immunological findings in cigarette smokers. Toxicology Letters, 118(3), 121–127. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/11137318
Platonova, S., Cherfils-Vicini, J., Damotte, D., Crozet, L., Vieillard, V., Validire, P., … Cremer, I. (2011). Profound coordinated alterations of intratumoral NK cell phenotype and function in lung carcinoma. Cancer Research, 71(16), 5412–5422. https://doi.org/10.1158/0008-5472.CAN-10-4179
Tonn, T., Schwabe, D., Klingemann, H. G., Becker, S., Esser, R., Koehl, U., … Bug, G. (2013). Treatment of patients with advanced cancer with the natural killer cell line NK-92. Cytotherapy, 15(12), 1563–1570. https://doi.org/10.1016/j.jcyt.2013.06.017
Yang, L., Wang, L., & Zhang, Y. (2016). Immunotherapy for lung cancer: advances and prospects. American Journal of Clinical and Experimental Immunology, 5(1), 1–20. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/27168951
Zhang, G., Zhao, H., Wu, J., Li, J., Xiang, Y., Wang, G., … Jiao, S. (2014). Adoptive immunotherapy for non-small cell lung cancer by NK and cytotoxic T lymphocytes mixed effector cells: retrospective clinical observation. International Immunopharmacology, 21(2), 396–405. https://doi.org/10.1016/j.intimp.2014.04.026