In a new study, researchers from UCL Cancer Institute have found that a subset of immune cells are capable of killing cancer cells when they are activated. This could lay the foundation stone for effective anti-cancer therapies believe the researchers.
Image Credit: Christoph Burgstedt / Shutterstock.com
The study titled, "Regulatory T cells restrain Interleukin-2 and Blimp-1-Dependent acquisition of cytotoxic function by CD4+ T cells" was published in the latest issue of the journal Immunity on the 7th of January 2020.
Activation of immune cells upon immunotherapy
This study was led by Professors Sergio Quezada and Karl Peggs, who had conducted previous research on the same theory, have found that when the immune system is subjected to immunotherapy, some of the cells are activated.
These activated CD4+ T cells were initially thought to be helper cells and regulate the immune cells. When activated, these cells have been found to become killer cells and directly kill the cancer cells. This has been proven in animal studies on lab mice, the authors wrote.
The study funded by the Cancer Research UK was an in-depth analysis of what happened at the cellular level, in order to see what the immune cells do to cancer cells. The cellular mechanisms of these activities have been outlined in this research.
Results revealed that in the T cells, a growth factor called Interleukin 2 (IL-2) was the main factor behind the cytotoxic or cell killing activities. This was aided by the 'transcription factor' Blimp-1. Both of these factors are responsible for starting the killer activities of the CD4+ T cells within the cancers.
We knew these immune cells had the ability to proactively kill cancer cells with incredible potency, but to maximize their potential, we needed to know how this mechanism was activated. Our discovery provides the evidence and rationale for utilising Blimp-1 to maximise the anti-tumour activity of CD4+ T cells. Work is now underway in our lab to develop new personalized cell therapies where the activity of Blimp-1 can be maxed up to drive potent tumor control."
Professor Sergio Quezada, UCL Cancer Institute
The team explained that T-type lymphocytes are generally the attacker cells of the immune system, killing infected cells around the body. These cells, however, are normally incapable of killing cancer cells because cancer cells are made up of the body's own cells. When these T cells are activated using immunotherapy, they are modified so that they can attack cancer cells. The actual challenge of immunotherapy thus lies in activating the T cells, explained the researchers.
Mouse models of cancer
The team used transplantable and autochthonous mouse models of cancer, wrote the researchers. They explained, "CD4+ T cells play a key role in the regulation of immune responses to self and foreign antigens, differentiating into various subsets of helper and regulatory T cells and instructing the function of CD8+ T cells, NK cells and macrophages.
Nonetheless, little is still know about the biology of tumour-reactive CD4+ T cells during tumour progression and cancer immunotherapy. Most importantly, we recently demonstrated that tumor-reactive CD4+ T cells can also acquire granzyme-dependent cytotoxic activity and directly target and kill tumor cells in vivo." This study was thus undertaken to see how the functions of these tumor-reactive CD4 T cells could be controlled and modified.
The team concluded that the tumor-infiltrating CD4 + T cells demonstrate T helper and cytotoxic features. Further Treg (T regulatory cells) cells reduce the availability of IL-2, which is essential for cytotoxic features of the T cells.
They write that T-bet is required for Interferon Gamma (IFN-γ) expression within the CD4+ cells. On the one hand, Blimp-1 is required for GzmB (granzyme B) expression in the T cells when stimulated by IL2, but T-bet is not needed for GzmB expression.
Applying these results to therapies
Professor Karl Peggs said in his statement, "Cellular therapies have only recently entered the mainstream in terms of clinical application. Much remains unknown regarding how best to optimise these therapies, particularly to enable better activity in solid organ cancers. Our findings broaden our understanding of the regulators of T cell differentiation, illuminating new elements that might be targeted to enhance therapeutic efficacy."
From Cancer Research UK, Dr. Emily Farthing, research information manager said in her statement, "Research like this helps scientists better understand the intricacies of our immune system and how it can be utilized to kill cancer cells. This work in the lab adds to growing evidence for the potential of immunotherapy and will hopefully lead to the development of more effective treatments for people affected by cancer."
Śledzińska, A. et al. (2020). Regulatory T Cells Restrain Interleukin-2- and Blimp-1-Dependent Acquisition of Cytotoxic Function by CD4+ T Cells. Immunity. DOI: https://doi.org/10.1016/j.immuni.2019.12.007