T cell exhaustion in CLL

Interaction of B7/CD28 family members are known to regulate and fine-tune the magnitude and quality of T cell responses. Recently, a novel inhibitory receptor on T cells PD-1 (CD279) was shown to interact with two B7 receptor family members PD-L1 (B7-H1; CD274) and PD-L2 (B7-DC; CD273). Originally , it was described that PD-1 is expressed following T cell activation and mediates peripheral T cell tolerance upon interaction with PD- L1/2 expressing target cells. Novel findings have shown that viruses and some tumours exploit the PD-1/PD-L pathway for immune evasion by tolerogenizing specific T cells to induce a state termed "T cell exhaustion", characterized by constitutive expression of PD-1, ablation of cytokine production and decreased proliferative potential. Chronic lymphocytic leukaemia (CLL) is a B cell malignancy marked by accumulation of monoclonal CD5+ CD19+ B cells in blood and lymphoid organs. Although CLL is a B cell lymphoma, early studies in our laboratory and from other groups have pointed to T cell involvement in disease progression and tumour growth. Based on these findings, we started to phenotypically characterize T cells from CLL patients in regard to T cell exhaustion and found a significant higher proportion of exhausted T cells in CLL patients compared to healthy individuals. From these preliminary data, we now propose a project that aims at elucidating the significance of exhausted T cells for CLL using primary patients` samples as well as a mouse model for this disease. Since CLL is still incurable, our findings will be crucial for a deeper understanding of this disease and for the development of new therapeutic approaches.

T cell exhaustion is the functional silencing of antigen experienced T cells, contributing to peripheral T cell tolerance to avoid extensive immune pathology during T cell responses. T cell exhaustion was initially reported for virus specific T cells upon chronic infection, such as HIV or CMV. However, T cell exhaustion was also found to occur in cancer and is supposed to significantly contribute to immune evasion of cancer cells by rendering cancer specific T cells non-functional. A key molecule in T cell exhaustion was found to be programmed death-1 (PD-1), which functionally impedes T cell receptor mediated signaling on exhausted T cells. In addition to PD-1, a number of different inhibitory receptors were recently found to be associated with T cell exhaustion. The concept that the exhausted phenotype could be reversed by simply blocking these inhibitory receptors with monoclonal antibodies led to a renaissance of cancer immune therapy with specific immune checkpoint blockade using PD-1 antibodies being considered as a major breakthrough in cancer treatment. In this project, we were able to gain new insight into T cell exhaustion in chronic lymphocytic leukemia and contributed to a better understanding regarding receptor composition and reactivability of silenced T cells intending to increase efficacy and efficiency of future checkpoint inhibition strategies.