Posted on 28 March 2022
Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.
Why is this research important: Certain cancers can now be treated by taking the patient’s white blood cells – specifically, their T cells – and genetically engineering them to recognise molecules that are highly expressed by cancer cells. These T cells, known as chimeric antigen receptor T cells (CAR T cells), are then injected back into the patient, and are then able to recognise and destroy cancer cells while leaving normal cells untouched. CAR-T cell therapy has great potential for treating cancers and potentially other diseases as well. Unfortunately, CAR T cells often don’t persist for long enough within the patient’s body, resulting in relapses. This is partly because cancer cells are able to suppress the activity of T cells, causing them to become dysfunctional.
What did the researchers do: In this study, researchers wanted to find human genes that might increase the persistence of T cells. To do this, they used lentiviruses to introduce copies of about 12 000 human genes into cultured human T cells from three donors. They then selected those T cells that proliferated the most when stimulated. As each gene carried by the lentiviruses had been ‘barcoded’ (tagged with a short, unique DNA sequence) they were able to see which of the 12 000 genes were most frequently present in the proliferating cells.
After identifying the top ranked genes, they took T cells from a new set of donors and studied the effects of introducing those genes, including their ability to attack cancer cells after being made into CAR T cells.
Key takeaway(s) from this research: Interestingly, the researchers found that the top ranked genes associated with increased T cell proliferation also improved other aspects of T cell function – particularly the highest ranked gene called LTBR. This LTBR gene, which is not usually expressed by T cells, increased the production of two signalling molecules that are important for T cell activity (interferon gamma and interleukin 2), and also increased the expression of hundreds of genes that play a role in T cell activity. Notably, T cells expressing LTBR were less likely to self destruct (apoptosis) or become dysfunctional after being chronically exposed to antigens.
When the researchers made CAR T cells using FDA-approved approaches, then combined these cells with their top-ranked genes, they found that the CAR T cells were more effective at killing blood cancer cells (B cell leukaemia) in culture for 6 out of 7 genes tested. Below is a video of regular and LTBR-expressing CAR T cells in action, with the cancer cells labelled in green.
All currently FDA-approved CAR T cell therapies use a lentivirus or similar virus to produce the therapeutic cells. Since this is the same approach used to introduce the genes in this study, making enhanced CAR T cells for human cancer treatment using these genes shouldn’t be a major regulatory or manufacturing problem. The researchers hope that their methods can be applied to find more genes that could be used to help CAR T cells overcome suppression by cancer cells.
A genome-scale screen for synthetic drivers of T cell proliferation: https://doi.org/10.1038/s41586-022-04494-7