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User:Nthoma4/Lymphokine-activated killer cell

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Lymphokine-activated killer cell

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In cell biology, a lymphokine-activated killer cell (also known as a LAK cell) is a white blood cell, related to the natural killer, natural killer T, and T cells, that has been stimulated to kill tumor cells. Because of the function in which they activate, their cell surface phenotype, and the range of cells they target, LAK cells are classified as distinct from the natural killer and T lymphocyte systems. They possess the ability to lyse fresh tumor cells, while fresh normal cells are unaffected by their lytic activity.[1] Activation of LAK immune cells is stimulated by the lymphokine Interleukin-2, a key regulator of lymphocytes which in itself is approved for the treatment of certain cancers both as a monotherapy and in combination with other cancer immunotherapies.[2]

Mechanism

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Visualization of LAK cell activity. Injection of LAK cells and IL-2 in murine lungs inhibit metastatic sarcoma tumor growth, visible as white nodules. Top and bottom leftmost lungs injected with saline; rightmost sets of lungs injected with LAK cells and IL-2.

Lymphocytes, such as human peripheral blood lymphocytes (PBL), cultured in the presence of IL-2 results in the development of a unique type of effector cell: the LAK cell. These cytotoxic effector cells are observed to localize at tumor sites and are capable of lysing fresh, non-cultured cancer cells, both primary and metastatic.[3] After activation by IL-2, LAK cells acquire cell surface markers characteristic of T-cells, which contribute to their targeting capability during the early innate response.[4] [5]

The mechanism of LAK cells is distinctive from that of natural killer cells, which cannot lyse many of LAK cell targets. LAK cells are also capable of acting against cells that do not display the major histocompatibility complex, as has been shown by the ability to cause lysis in non-immunogenic, allogeneic, and syngeneic tumors. LAK cells function in the same way as NK cells in the peripheral blood but provide a more capable defense against tumor cells.

History of LAK Cells

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LAK cells were first generated in 1980 from lymphocytes exposed to lymphokine IL-2, with the goal of creating an immune cell with the ability to target a wide range of human tumors. The novel method involved the incubation of murine splenocytes and human lymphocytes in IL-2-containing supernatants. The resulting cells were found to be lytic to fresh tumor cells, but not normal cells. It was determined through further experimentation that IL-2 was activating the lytic activity of the cells.[6]

Following their initial creation, LAK cells drew intrigue for in vitro murine and human studies. LAK cellular activity was distinguished from NK cells and established as their own type of immune cell. One study observed the generation of LAK and NK cells in immunodeficient mice, and found varying activity of each at the experiment endpoint. After in vitro incubation of lymphoid cells in recombinant IL-2 (RIL-2), mouse splenocytes showed NK activity, but an inability to generate LAK cells, while a different set of mice showed generation of LAK cells in their splenocytes and no NK cell activity.[7] Another study determined the ability of LAK cells to lyse various human tumors resistant to NK cell activity.

Through the early 80's, in vivo murine studies were being conducted using LAK cells. Typically, LAK activation was conducted over the course of three days in vitro before the adoptive transfer of LAK cells into murine models. LAK cells showed therapeutic promise when implanted with IL-2 cells into mice, encouraging the development of human clincal trials performed in 1984.[5]

Cancer Treatment

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Through a process called adoptive cell transfer, LAK cells implanted to a tumor-bearing organism have been observed to reduce metastatic progression. In one study, LAK cells were introduced to sarcoma- or adenocarcinoma-bearing mice with substantial lung, liver, or subcutaneous metastasis. Alone, LAK cells did not show any significant tumor reduction, but when implanted with additional IL-2, there was a reduction in metastatic progression. The adoptive transfer of both LAK cells and IL-2 was deemed most efficacious when additionally paired with prior intervention, such as surgery or chemotherapy, to reduce the size of the tumor.[8]

The use of lymphokine activated killer cells has been found to be helpful in treating human cells with different cancers in vitro[9]. LAK cell therapy is a method that uses interleukin 2 (IL-2) to enhance the number of lymphocytes in an in vitro setting, and it has formed the foundation of many immunotherapy assays that are now in use[10]. LAK cells have shown potential as a cellular agent for cancer therapy and have been utilized therapeutically in association with IL-2 for the treatment of various cancers. LAK cells have anticancer efficacy against homologous carcinoma cells and can grow ex vivo in the presence of IL-2[11]. Studies have revealed an anti-tumor mechanism in which ICAM1 in lung cancer cells increases LAK cell-mediated tumor cell death in melanoma and gastric cancer cells. The upregulation of intercellular adhesion molecule 1 (ICAM-1) can significantly accelerate in vitro LAK-induced lysis of these cancer cells.[12] One study utilized a 4 hour chromium release assay, which is an assay commonly used to measure the cytotoxicity of T cells and natural killer cells, to measure lysis of the fresh solid tumor cells from 10 cancer patients. It was found that in all 10 cancer patients, the fresh autologous tumor cells were resistant to lysis by natural killer cells, but were lysed by the LAK cells.[13]

Treatment Possible Side Effects

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LAK cells, along with the administration of IL-2 have been experimentally used to treat cancer in mice and humans, but there is very high toxicity with this treatment - Severe fluid retention was the major side effect of therapy, although all side effects resolved after interleukin-2 administration was stopped. Treatment of IL-2 cells by themselves to treat cancers are more dangerous than treatment with the combination of IL-2 and LAK cells.[14]

LAK cells undergo the normal process of apoptosis, though rapid rates of apoptosis are induced after interactions with tumor cells. This potentially explains why LAK cells may not be effective in certain therapeutic strategies.[15]

Notes and references

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  1. ^ Grimm, E. A. (1986-12-17). "Human lymphokine-activated killer cells (LAK cells) as a potential immunotherapeutic modality". Biochimica Et Biophysica Acta. 865 (3): 267–279. doi:10.1016/0304-419x(86)90017-x. ISSN 0006-3002. PMID 3539198.
  2. ^ Jiang, Tao; Zhou, Caicun; Ren, Shengxiang (2016-04-25). "Role of IL-2 in cancer immunotherapy". Oncoimmunology. 5 (6): e1163462. doi:10.1080/2162402X.2016.1163462. ISSN 2162-4011. PMC 4938354. PMID 27471638.
  3. ^ Grimm, E. A.; Mazumder, A.; Zhang, H. Z.; Rosenberg, S. A. (1982-06-01). "Lymphokine-activated killer cell phenomenon. Lysis of natural killer-resistant fresh solid tumor cells by interleukin 2-activated autologous human peripheral blood lymphocytes". The Journal of Experimental Medicine. 155 (6): 1823–1841. doi:10.1084/jem.155.6.1823. ISSN 0022-1007. PMC 2186695. PMID 6176669.
  4. ^ West, E., Scott, K., Jennings, V. et al. Immune activation by combination human lymphokine-activated killer and dendritic cell therapy. Br J Cancer 105, 787–795 (2011). https://doi.org/10.1038/bjc.2011.290
  5. ^ a b "Lymphokine-activated killer cells: A new approach to immunotherapy of cancer". academic.oup.com. doi:10.1093/jnci/75.4.595.
  6. ^ "Lymphokine-activated killer cells: A new approach to immunotherapy of cancer". JNCI: Journal of the National Cancer Institute. 01 October 1985. doi:10.1093/jnci/75.4.595. ISSN 1460-2105. {{cite journal}}: Check date values in: |publication-date= (help)
  7. ^ Andriole, G L; Mulé, J J; Hansen, C T; Linehan, W M; Rosenberg, S A (1985-11-01). "Evidence that lymphokine-activated killer cells and natural killer cells are distinct based on an analysis of congenitally immunodeficient mice". The Journal of Immunology. 135 (5): 2911–2913. doi:10.4049/jimmunol.135.5.2911. ISSN 0022-1767.
  8. ^ Herberman, Ronald B. (1998-01-01), Delves, Peter J. (ed.), "Lymphokine-Activated Killer (LAK) Cells", Encyclopedia of Immunology (Second Edition), Oxford: Elsevier, pp. 1627–1631, ISBN 978-0-12-226765-9, retrieved 2024-05-04
  9. ^ Rosenberg SA. IL-2: the first effective immunotherapy for human cancer. J Immunol. 2014 Jun 15;192(12):5451-8. doi: 10.4049/jimmunol.1490019. PMID: 24907378; PMCID: PMC6293462.
  10. ^ Maeta N, Tamura K, Takemitsu H, Miyabe M (July 2019). "Lymphokine-activated killer cell transplantation after anti-cancer treatment in two aged cats". Open Veterinary Journal. 9 (2): 147–150. doi:10.4314/ovj.v9i2.9. PMC 6626148. PMID 31360654.
  11. ^ Jennings VA, Ilett EJ, Scott KJ, West EJ, Vile R, Pandha H, et al. (March 2014). "Lymphokine-activated killer and dendritic cell carriage enhances oncolytic reovirus therapy for ovarian cancer by overcoming antibody neutralization in ascites". International Journal of Cancer. 134 (5): 1091–1101. doi:10.1002/ijc.28450. PMC 4321045. PMID 23982804.
  12. ^ Haustein M, Ramer R, Linnebacher M, Manda K, Hinz B (November 2014). "Cannabinoids increase lung cancer cell lysis by lymphokine-activated killer cells via upregulation of ICAM-1". Biochemical Pharmacology. 92 (2): 312–325. doi:10.1016/j.bcp.2014.07.014. PMID 25069049.
  13. ^ West, E., Scott, K., Jennings, V. et al. Immune activation by combination human lymphokine-activated killer and dendritic cell therapy. Br J Cancer 105, 787–795 (2011). https://doi.org/10.1038/bjc.2011.290
  14. ^ Rosenberg SA, Lotze MT, Yang JC, Aebersold PM, Linehan WM, Seipp CA, White DE. Experience with the use of high-dose interleukin-2 in the treatment of 652 cancer patients. Ann Surg. 1989 Oct;210(4):474-84; discussion 484-5. doi: 10.1097/00000658-198910000-00008. PMID: 2679456; PMCID: PMC1357927.
  15. ^ Taga, K.; Yamauchi, A.; Bloom, E. T. (1999-02). "Target cell-induced apoptosis in IL-2-activated human natural killer cells". Leukemia & Lymphoma. 32 (5–6): 451–458. doi:10.3109/10428199909058402. ISSN 1042-8194. PMID 10048417. {{cite journal}}: Check date values in: |date= (help)
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