| dc.description.abstract | Relevance and explanation
Immune checkpoint inhibitors (ICI) are a potent treatment against cancer. The immune system has immune checkpoints in place to keep the balance between inducing an immune response and maintaining tolerance. Cancer can exploit these immune checkpoints by inducing tolerance, making it hard for the immune cells to effectively clear cancer cells. ICI were developed to block this cancer-induced tolerance and unleash a potent anti-tumour immune response. This treatment has proved to be very efficacious and has transformed the field of cancer treatment. However, not all patients are responsive, and the treatment is often accompanied by toxicities called immune-related adverse events (irAEs). ICI-induced toxicity is partly dependent on the type of ICI treatment. Still, most patients develop an irAE ranging from mild to lethal, independent of treatment type. The current treatment of these irAEs is with immunosuppressants that dampen the immune response alongside with the anti-tumour response. This calls for alternative treatment strategies for irAEs. In addition, we must find tools that can guide clinicians in assessing what (ICI) treatment is most beneficial for the patient, concerning response and the risk of developing toxicity.
Aim of study
Comparing the dynamics of T cells in patients’ blood, before and during treatment, could clarify some of the underlying mechanisms in ICI treatment regarding response and toxicity. It might also aid in finding potential biomarkers that predict toxicity and treatment outcomes. Additionally, it could help identify new targets in the treatment of irAEs.
Study design
In this study, we investigated the peripheral T cell responses of cancer patients under treatment with ICI. We used the blood samples of cancer patients receiving two different types of ICI treatment: monotherapy or combination therapy. Within these two groups, half of the patients developed irAEs that required medical attention, while the other half did not. We assessed the immune cells retrieved from their blood samples, taken before they started treatment and after the first and second dose, or when they developed toxicity.
Results
We found that an increased CD4+/CD8 +T cell ratio is increased in patients that respond to treatment without developing toxicity. Secondly, we found that the levels of LAG-3+CD8+ T cells were elevated at baseline, in patients without clinical benefit. This subset could have potential predictive value in treatment outcomes. ICI treatment induced a stronger decrease in IFN-y-expressing CD8+ T cells in toxicity-developing patients. More CD8+ T cells expressing co-inhibitory receptors, unable to produce IFN-y were also observed in this group. Granzyme- B-producing PD-1+, LAG-3+, and memory CD8+ T could be associated with toxicity and its severity. Combination therapy induced more (PD-1+)CD4+ memory T cells compared to monotherapy which could possibly contribute to toxicity development as well.
Conclusion
We identified interesting trends in peripheral T cell responses related to toxicity and response. These findings will need to be confirmed and clarified in further research but could contribute to the knowledge of the underlying mechanisms in ICI treatment, as well as aid in the search for predictive biomarkers for toxicity and response. | |
