HomeENGLISH MAGAZINECheckpoint reviewed: T-regulating subsets struggling between right fight and self-destruction

Checkpoint reviewed: T-regulating subsets struggling between right fight and self-destruction

T cells may be best known for their roles in fighting infections and killing cancer cells. But the immune system also has several mechanisms in place to counterbalance those responses to prevent out-of-control inflammation that could damage healthy tissue. Tregs are one aspect of this balancing act. Tregs may be viewed as the health and safety inspectors of the immune system. They’re really important, but sometimes, to mount an immune response against a pathogen, there is also a need them to take a back seat. With an infection ongoing, scientists had seen Treg levels crash so that an effector response can emerge. But they never understood what causes that crash. A similar and more complex response happens with cancer: form one side there is the nedd for immune cells to uproot cancer; on the other, cancer tries every strategy to evade immune response and undergoes deregulation with the balance of the lymphocyte populations.

Checkpoint inhibitors have become important tools in the cancer-fighting arsenal. By blocking proteins that normally restrain the immune response, these drugs can help the immune system destroy cancer cells. But they don’t work in all patients. And now a new study led by researchers from Penn’s School of Veterinary Medicine, suggests what is lying beneath: not only can these drugs encourage the activity of cancer killing T cells, but they can, in some cases, also activate a population of regulatory T cells that serve the opposing function, that is to rein in that attack.In the study, scientists discovered that blocking the activity of the checkpoint protein PD-L1, which interacts with a T cell receptor PD-1, enhanced the activity of a subset of T cells known as effector regulatory T cells, or effector Tregs. This intervention unexpectedly reduced the ability of mice to control a parasite infection.

The researchers began to understand more after exploring an unanticipated finding. They discovered that, when PD-L1 was blocked, mice infected with Toxoplasma gondii were less effective at fighting off the parasite than mice with an uninhibited PD-L1. Which is exactly the opposite of what was to be expected, as the current knowledge would have suggested that blocking this checkpoint inhibitor should allow for a better effector T cell response against infection. Digging into the surprising result, the researchers realized that it aligned with what some cancer researchers had recently reported. In certain cancers, the other groups had found, blocking PD-L1 led to worse outcomes, seemingly because of an increase in a population of Tregs that restrained killing of cancer cells. When the team looked in the context of a Toxoplasma infection, they discovered the cytokine interferon gamma turned on PD-L1, which precipitated a rapid decline in Treg numbers.

A PD-L1 inhibitor mitigated this effect and stopped the Treg crash. This treatment alleviated the harmful effects of inflammation on mice but also impaired the ability of T cells to fight the infection as well. Similarly, Tregs altered to lack PD-1, the PD-L1 receptor, also led to increases in Treg activity. Finbally the researchers wondered about whether this pathway worked when animals were in a normal, healthy state. Just as there are different types of “regular” T cells, including CD8 and CD4 T cells and many more subdivisions besides, the new work underscores that there are subpopulations of Tregs as well, which have different roles in the body. In healthy, uninfected animals, the team found differences between the proteins expressed by different Treg populations, including some lymphocytes that expressed PD-1 termed “effector Tregs. These results indicates that there’s a large population of activated PD-1-positive Treg cells present as a normal part of everyday life that help limit the immune system.

Due to these complexities, the research team deem that it is possible that some checkpoint inhibitor treatments have been inadvertently targeting these Tregs and not others, leading to unexpected outcomes. The discovery could have implications not only in refining cancer checkpoint inhibitor therapies but also in conceiving new strategies for treating autoimmune diseases as well. The occurrence of immune-related adverse events in response to activation of the immune system by immunotherapy, is known to correlate with higher response to anti-PD-1 therapy and improved outcomes in patients with some cancers like lung carcinoma or melanoma. Moreover, combined blockade of PD-1 and a second immune checkpoint protein, such as CTLA-4, often results in better treatment outcomes but at the cost of increased risk of autoimmunity onset. Indeed, a research group of the Garvan Institute of Medical Research in Australia, last week presented a poster of preliminary data at the AACR 2022 Annual Meeting concerning this issue.

By genomic analysis, scientists found patients exhibiting exceptional response to anti-PD-1 therapy, defined as progression-free survival of at least two years and one or more immune-adverse events of grade 2 or higher. Among the polymorphisms (SNP) found, one of them was present in 15.7% of exceptional responders. This SNP has been reported to impact the function of the CTLA-4 immune checkpoint protein to drive increased susceptibility to autoimmune disease, such as rheumatoid arthritis and type 1 diabetes. As such, this CTLA-4 variant could be used to identify patients that would benefit from anti-PD-1 treatment. Identifying more genetic variants of immune proteins could also help us better understand the mechanisms underlying current variability in response and why some patients develop more severe autoimmune side effects following immune checkpoint therapy.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Perry JA et al. Nature Immunology 2022 Apr 18; 40:119.

Naimi A et al. Cell Commun Signal. 2022 Apr 7; 20(1):44.

Chow A, Schad S et al. Cancer Cell. 2021; 39(7):973-988.

Molina G, Zubiri L et al. Oncologist. 2021; 26(6):514-522.

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Dott. Gianfrancesco Cormaci

Medico Chirurgo, Specialista; PhD. a CoFood s.r.l.
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry residency in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Guardia medica presso strutture private dal 2010 - Detentore di due brevetti sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento enzimaticamente neutralizzata (owner of patents concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (Leader of the R&D for the partnership CoFood s.r.l.) - Autore di articoli su informazione medica e salute sul sito www.medicomunicare.it (Medical/health information on website) - Autore di corsi ECM FAD pubblicizzati sul sito www.salutesicilia.it
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