T cells and Cancer Treatment paper
Final Paper
Batonya Southerland
T cells and Cancer Treatment paper
Malignant transformation is the process by which cells acquire the properties of cancer. Malignant transformation is uncontrolled and has irreversible cell growth. Some characteristics of malignant transformation is the increase of proliferation, loss of inhibition, and loss of programmed cell death. According to Rodriguez and Ochoa (2016, p. 526-533), the malignant transformation of cells produces radical changes in their metabolism and the soluble factors they produce. These changes support rapid cell proliferation and facilitate their invasion into surrounding tissues as well as distant metastatic spread.
Cancer is an unchecked cell growth. Mutations in genes can cause cancer by accelerating cell division rates or inhibiting normal controls on the system, such as cell cycle arrest or programmed cell death. As a mass of cancerous cells grows, it can develop into a tumor (Nguyen, Bos, & Massagué, p. 274–284). Tumor cells appear to contain antigens that evoke a weak immune response. According to Tontonoz (2018), the immune system can clearly recognize cancer cells as different, yet often it is unable to stop them from growing. As reported by Hou, Xu, & Wang (2011, p.1-12), tumor antigens are those presented by MHC class I or II molecules on the surface of tumor cells. These antigens are sometimes presented only by tumor cells and never by normal cells. T cells recognize antigens with their antigen receptor. However, they do not recognize self-antigens. T cells recognize cells that contain foreign antigens as in, virally infected cells, foreign tissue grafts, tumor cells, etc. They also recognize small peptides from tumor antigens in association with MHC antigens. While B cells recognize the whole protein antigen.
In various types of cancer, the presence of high Treg cells and a low ratio of CD8+ T cells to Treg cells in the TME are associated with an unfavorable prognosis. In tumor immunity, Treg cells are involved in tumor development and progression by inhibiting antitumor immunity. Regulatory T cells are then activated and inhibit antitumor immune responses. A high infiltration by Treg cells is associated with poor survival in various types of cancer (Ohue & Nishikawa, 2019, p. 2080-2089). High levels of Tregs in the tumor microenvironment are associated with poor prognosis in many cancers, such as ovarian, breast, renal, and pancreatic cancer. This indicates that Tregs suppress T effector cells and hinder the body’s immune response against the cancer. The Treg cells, or regulatory T cells, are usually differentiated in the thymus by an intermediate range of signals. The naive T cells can be differentiated into regulatory cells by the presence of antigen in the small intestine. It occurs with the help of retinoic acid and TGF-beta (transforming growth factor) is produced by the dendritic cells which induce the differentiation into Treg cells. It maintains the barrier integrity and accelerates wound healing in this region. Dendritic cells are responsible for programming naïve T cells to become Treg cells.
According to Curiel, Coukos, Zou, Alvarez, Cheng, Mottram, Evdemon-Hogan, Conejo-Garcia, Zhang, Burow, et al. (2004, p. 942–949), regulatory T (Treg) cells mediate homeostatic peripheral tolerance by suppressing autoreactive T cells. Failure of host antitumor immunity may be caused by exaggerated suppression of tumor-associated antigen–reactive lymphocytes mediated by Treg cells. However, definitive evidence that Treg cells have an immunopathological role in human cancer is lacking.
A study showed CD4+CD25+FOXP3+ Treg cells in 104 individuals affected with ovarian carcinoma that human tumor Treg cells suppress tumor-specific T cell immunity and contribute to growth of human tumors in vivo. Treg cells are associated with a high death hazard and reduced survival. The primary function of Treg cells was originally defined as prevention of autoimmune diseases by maintaining self-tolerance. Over the years, several additional functions have been suggested and it will be important to clarify what Treg cells actually do in the immune system. Presently, at least 4 non-exclusive functions have been proposed for Treg cells: Prevention of autoimmune diseases by establishing and maintaining immunologic self-tolerance, Suppression of allergy and asthma, and the prevention of T cells that have been stimulated by their true high-affinity agonist ligand from killing cells that only express low-affinity T-cell receptor (TCR) ligands such as the self-peptide-major histocompatibility complex (MHC) molecule that positively selected the T cell (Corthay, 2009, p. 326-336).
Treg cells (CD4+CD25+FoxP3+) belong to the family of CD4+ T cells. As stated by Verma, Mathur, Farooque, Kaul, Gupta, & Dwarakanath (2019, p. 10731–10747) in vivo studies in mice models indicate that Tregs regulate concomitant immunity and cross-reactive anti-tumor immunity. Tregs not only suppress the natural killer (NK) cell-mediated cytotoxicity but also check the proliferation of CD4+ and CD8+ T-cells and inhibit the interferon (IFN)-γ secretion by immune cells, thereby leading to the impairment of effective anti-tumor immune response. Indeed, higher Tregs activity has been related to decreased survival and poor prognosis in patients of breast cancer, gastric carcinoma, non-small cell lung cancer (NSCLC), squamous cell carcinoma of head and neck (SCCHN), pancreatic cancer and ovarian cancer.
In accordance with Putnam, Brusko, Lee, Lui, Szot, Ghosh, Atkinson, & Bluestone (2009, p. 652–662), one major concern when proposing to expand Tregs from type 1 diabetic patients or other autoimmune subjects is the potential for outgrowth of activated Teff cells. In this study described herein, we present two protocols for isolating and expanding adult human Tregs from patients with recent-onset type 1 diabetes. They characterize the phenotypic and functional properties of these cells after in vitro expansion and suggest that these approaches lead to selective expansion of cells with immunosuppressive properties. Tregs were isolated from nine adult individuals with recent-onset type 1 diabetes. Control subjects lacked any autoimmune disorders or related probands with type 1 diabetes. Informed consent was obtained in accordance with approved policies and procedures.
Citations
Rodriguez, P., C. & Ochoa, A., C. (2016). Soluble mediators of immune suppression in the tumor microenvironment. Encyclopedia of Immunobiology4, 526-533.
Nguyen, D. X., Bos, P. D., & Massagué, J. (2009). Metastasis: From dissemination to organ-specific colonization. Nature 9, 274–284
Tontonoz, M. (2018). The immune system can fight cancer. So why doesn’t it? Memorial Sloan Kettering Cancer Center, https://www.mskcc.org/news/immune-system-can-fight-cancer-so-why-doesn-t-it#:~:text=The%20immune%20system%20can%20clearly,are%20trying%20to%20understand%20why.&text=Memorial%20Sloan%20Kettering%20scientists%20are,sometimes%20fail%20to%20fight%20cancer.
Hou, W., Xu, G., & Wang, H. (2011). CHAPTER 1 – Basic immunology and immune system disorders. Treating Autoimmune Disease with Chinese Medicine, 1-12.
Ohue, Y., & Nishikawa, H. (2019). Regulatory T (Treg) cells in cancer: Can Treg cells be a new therapeutic target? PMC 110, 2080-2089.
Curiel, T., J., Coukos, G., Zou, L., Alvarez, X., Cheng, P., Mottram, P., Evdemon-Hogan, M., Conejo-Garcia, J., R., Zhang, L., Burow, M., et al. (2004). Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nature medicine 10, 942–949.
Corthay, A. (2009). How do regulatory T cells work? PMC 70, 326-336.
Verma, A., Mathur, R., Farooque, A., Kaul, V., Gupta, S., & Dwarakanath B., S. (2019). T-regulatory cells in tumor progression and therapy. PMC 11, 10731–10747.
Putnam, A., L., Brusko, T., M., Lee, M., R., Lui, W., Szot, G., L., Ghosh, T., Atkinson, M., A., & Bluestone J., A. (2009). Expansion of human regulatory T-cells from patients with type 1 diabetes. PMC 58, 652–662.