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A Busy Bee: multifunctional IL-2 in the immune system and the immunotherapy

2022-07-06
We always hear about the Interleukin-2 (IL-2) while culturing the cells, including T cells, natural killer cells, and the cells of monocyte lineage.
And why is the IL-2 so popular? Let’s figure it out.
 
What’s the IL-2?
In the immune system, IL-2 is a T cell-derived cytokine and a cytokine signaling molecule. IL-2 is involved in the body's natural reaction to microbial infection as well as the distinction between "non-self" and "self." By interacting with IL-2 receptors, which are present on the surface of lymphocytes, IL-2 can exert its effects. Activated CD4+ T cells and activated CD8+ T cells are the primary sources of IL-2[1] but have been reportedly made by NK cells[2] and dendritic cells[3, 4] as well.



What’s the ability of IL-2?
The immune response is influenced by IL-2 in a pleiotropic way[5]. Its secretion is closely regulated and plays a role in immunological responses as part of both temporary positive and negative feedback loops.​
  • Augmenting NK cells and CD8+ T cells killing activity [6]
  • Promoting leukocytes and lymphocytes proliferation and differentiation
  • Suppressing the immune response of immune cells through activating regulatory T cells and further treating autoimmune diseases [7]
  • Encouraging or blocking different cytokine cascades [6]




How do IL-2 transmit the signals?
IL-2 signals with cells via heterotrimeric cell surface receptors, which are expressed by a variety of cells, such as lymphocytes. IL-2Rα (CD25), IL-2Rβ (CD122), and common γc (CD132) are the three subunits that form the IL-2 receptor. These subunits could assemble in various combinations, each with a different affinity, high, medium, and low. [8] Once IL-2 attaches to the IL-2 receptor, there would be three different signaling transduction that happened, AK-STAT, MAPK/ERK, and PI3K/Akt/mTOR.
 


How do biopharma and biotech companies apply IL-2 in immunotherapy now and in the future?

♦ Adoptive cellular therapy (ACT)
​IL-2 immunotherapy was reported in a number of clinical trials because of its capacity of expanding and activate a variety of cells. The most well-known one is to massively expand T cells, like tumor infiltrating cells (TIL) and TCR/CAR engineered T cells. For more than 20 years, ACT T cell cultures have been established and expanded using high doses of IL-2. [9] Meantime, T cells are forced to express IL-2 themselves which would prolong survival and sustain tumor specificity function as well.
IL-2 can also facilitate the differentiation of T cells which may lead to generating various types of T cells, such as regulatory T cells (Treg). Currently, Treg cells are being explored as a potential treatment for autoimmune diseases and graft rejection.[10] However, the research showed that Treg cells are not suitably maintained under inflammatory conditions as their pro-inflammatory characteristics would augment the autoimmune response. So, researchers prefer to do the in vivo Treg cell-based therapy via a low dose of IL-2 induced Treg than ACT.
In the recent studies, there is a subset of unconventional T cells, Vγ9Vδ2 T cells (γδT cells), have gained lots of attention as an intriguing tool for immunotherapy by ACT. γδT cells can display a strong anti-tumor activity. Most of the studies conducted γδT cells expansion only use IL-2 which is important to the effector of the γδT cells.[11]
In addition to CD8+ T cells with cytotoxic activity, NK cells also play an important role against cancer cells. It has been shown that T cell-derived IL-2 can activate NK cells in vitro. Although the development of NK cells is no need for IL-2 stimulation, it is essential for the effector function of the NK cells.[12]




♦ IL-2 Administration
As we mentioned above, IL-2 is a crucial cytokine when doing the ACT. In fact, in 1992, the first IL-2 treatment was approved by the FDA. The administration of IL-2 and the adoptive transfer of anticancer T lymphocytes cultured in high dose IL-2 are successfully in curing meta-static renal cell carcinoma and melanoma.[9]
However, the high dose of IL-2 requirement would lead to toxicity and serious side effects for the patients, such as inflammation and vascular leak syndrome. [13] Also, the short half-life of IL-2 could be the limitation of widely used in cancer therapy. In the past three decades, the researchers are dedicated to modifying the IL-2 signal transduction via engineering methods, pharmacokinetics properties….and so on. [14] Researchers recently fuse low-affinity IL-2 (laIL-2) with an anti–PD-1 antibody (PD-1–laIL-2) to target intratumoral T cells. LaIL-2 shows decreased binding to IL-2Rα and IL-2 Rβ, which would reduce unfavorable binding in the tumor and peripheral. On the other hand, tumor-infiltrating CD8+ T cells express high levels of PD-1. Respectively, PD-1–laIL-2 was more interested in intratumoral CD8+ T cells than Treg cells or peripheral CD4+ and CD8+ T cells. Even though the fact that this research is still in the animal model stage, these encouraging findings imply that PD-1–laIL-2 treatment could benefit cancer patients. [15, 16]





 




Ref.
  1. Liao W, Lin JX, Leonard WJ. IL-2 family cytokines: new insights into the complex roles of IL-2 as a broad regulator of T helper cell differentiation. Curr Opin Immunol. 2011 Oct;23(5):598-604.
  2. Miller JS, Tessmer-Tuck J, Blake N, Lund J, Scott A, Blazar BR, Orchard PJ. Endogenous IL-2 production by natural killer cells maintains cytotoxic and proliferative capacity following retroviral-mediated gene transfer. Exp Hematol. 1997 Oct; 25(11):1140-8.
  3. Granucci, F., C. Vizzardelli, N. Pavelka, S. Feau, M. Persico, E. Virzi, M. Rescigno, G. Moro, P. Ricciardi-Castagnoli. 2001. Inducible IL-2 production by dendritic cells revealed by global gene expression analysis. Nat. Immunol. 2:882.
  4. Zelante T, Fric J, Wong AY, Ricciardi-Castagnoli P. Interleukin-2 production by dendritic cells and its immuno-regulatory functions. Front Immunol. 2012 Jun 18;3:161.
  5. Valle-Mendiola A, Gutiérrez-Hoya A, Lagunas-Cruz Mdel C, Weiss-Steider B, Soto-Cruz I. Pleiotropic Effects of IL-2 on Cancer: Its Role in Cervical Cancer. Mediators Inflamm. 2016;2016:2849523.
  6. Liao W, Lin JX, Leonard WJ. Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy. Immunity. 2013;38(1):13-25.
  7. Graßhoff H, Comdühr S, Monne LR, Müller A, Lamprecht P, Riemekasten G, Humrich JY. Low-Dose IL-2 Therapy in Autoimmune and Rheumatic Diseases. Front Immunol. 2021 Apr 1;12:648408.
  8. Kim HP, Imbert J, Leonard WJ. Both integrated and differential regulation of components of the IL-2/IL-2 receptor system. Cytokine Growth Factor Rev. 2006 Oct;17(5):349-66.
  9. Rosenberg SA. IL-2: the first effective immunotherapy for human cancer. J Immunol. 2014 Jun 15;192(12):5451-8.
  10. Selck C, Dominguez-Villar M. Antigen-Specific Regulatory T Cell Therapy in Autoimmune Diseases and Transplantation. Front Immunol. 2021 May 14;12:661875.
  11. Peters C, Kouakanou L, Oberg HH, Wesch D, Kabelitz D. In vitro expansion of Vγ9Vδ2 T cells for immunotherapy. Methods Enzymol. 2020;631:223-237.
  12. Kündig TM, Schorle H, Bachmann MF, Hengartner H, Zinkernagel RM, Horak I. Immune responses in interleukin-2-deficient mice. Science. 1993 Nov 12;262(5136):1059-61.
  13. Pachella LA, Madsen LT, Dains JE. The Toxicity and Benefit of Various Dosing Strategies for Interleukin-2 in Metastatic Melanoma and Renal Cell Carcinoma. J Adv Pract Oncol. 2015 May-Jun;6(3):212-21.
  14. MacDonald A, Wu TC, Hung CF. Interleukin 2-Based Fusion Proteins for the Treatment of Cancer. J Immunol Res. 2021 Nov 8;2021:7855808.
  15. Ren Z, Zhang A, Sun Z, et al. Selective delivery of low-affinity IL-2 to PD-1+ T cells rejuvenates antitumor immunity with reduced toxicity. J Clin Invest. 2022;132(3):e153604.
  16. Holcomb EA, Zou W. A forced marriage of IL-2 and PD-1 antibody nurtures tumor-infiltrating T cells. J Clin Invest. 2022;132(3):e156628.
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