Michael Dudek, a research group lead at the Technical University of Munich, delivered a presentation on the mechanisms of tumour susceptibility to CD8 T cell-mediated killing, focusing on both antigen-specific and antigen-independent pathways. Dudek began by outlining the challenges posed by the tumour microenvironment, such as nutrient availability, inhibitory receptor expression, and cytokine presence, all of which can influence CD8 T cell function. The central theme of the presentation was the discovery and characterisation of antigen-independent cytotoxicity by CD8 T cells, a phenomenon first observed in the context of fatty liver disease and now being explored in cancer and inflammatory bowel disease.
Dudek’s group utilised K562 cells, which lack MHC Class I molecules, to demonstrate that CD8 T cells isolated from inflamed tissue of IBD patients could kill target cells independently of MHC Class I. This cytotoxicity was shown to be transient and dependent on IL-15 stimulation. Notably, these CD8 T cells exhibited killing dynamics similar to NK cells when exposed to IL-15. The group further identified that histones released from target cells could activate these IL-15-licensed CD8 T cells, triggering degranulation and cytotoxicity without the need for antigen recognition.
A key advancement presented was the identification of a specific, histone-triggered signalling pathway responsible for this antigen-independent killing. The pathway can be selectively inhibited without affecting antigen-specific CAR T cell activity, suggesting therapeutic potential for targeting pathogenic cytotoxicity while preserving beneficial immune responses.
Dudek’s ongoing research investigates whether this mechanism can be harnessed for anti-cancer immunity. The group has developed a gene signature to identify CD8 T cells with this function in tumour samples and found a correlation between the presence of these cells and improved responses to immune checkpoint blockade therapy. Additionally, the group observed that interferon alpha responses in tumours are associated with better immunotherapy outcomes, likely due to increased antigen presentation.
In summary, Dudek’s work highlights a novel layer of CD8 T cell cytotoxicity that operates independently of antigen recognition, with promising implications for enhancing cancer immunotherapy and understanding immune-mediated tissue damage.
