Targeting immune checkpoints in cancer: new mechanistic insights
Session type: Symposia
The continual interplay between the immune system and cancerous cells is thought to result in the establishment of a dynamic state of equilibrium. This equilibrium depends on the balance between subsets of effector and regulatory lymphocytes. Whereas the overall mechanisms underpinning the establishment and maintenance of the intra-tumour balance between Teff and Treg cells remain unknown, in many solid cancers it is characterised by the dominant infiltration of regulatory T cells over effector T cells resulting in a low Teff/Treg ratio. Furthermore, different subtypes of regulatory cells and inhibitory molecules such as CTLA-4 tightly control the few effector T lymphocytes that manage to infiltrate the tumour. The outcome of this balance is critical to survival, and while in a few cases the equilibrium resolves in the elimination of the tumour by the immune system, in many other cases the tumour manages to escape immune control.
Remarkably, antibodies against CTLA-4, a key immune modulatory receptor expressed on T cells, efficiently modify this balance, driving effector T cell expansion and increasing the ratio of Teff/Treg within the tumour. Whilst the high Teff/Treg ratio driven by anti-CTLA-4 directly correlates with tumour destruction in mice and humans, the mechanisms underpinning this phenomenon remain unknown.
By focusing in the study of effector and regulatory tumour-reactive CD4+ T cells my group is interested in the mechanism underpinning the activity of different immune-modulatory antibodies within the tumour microenvironment, and the potential positive and negative impact that the tumour microenvironment may have in the recruitment, survival and function of different T cell subsets. In this context and using a murine model of melanoma we have recently demonstrated that both the change in the Teff/Treg balance as well as tumour rejection depend on the selective depletion of tumour-infiltrating Treg cells expressing high levels of surface CTLA-4. Regulatory T cell depletion is mediated by ADCC and completely depends on the expression of Fc gamma RIV on tumour infiltrating CD11b+ myeloid cells. These results reveal novel and unexpected mechanistic insight into the activity of anti-CTLA-4-based cancer immunotherapy, and illustrate the importance of specific features of the tumour microenvironment on the final outcome of antibody-based immune-modulatory therapies.