Investigation of the role of γδ T-cells in melanoma rejection under checkpoint therapy

A crucial contribution of T-cells to cancer immunosurveillance and therapy has  been intensively studied and documented over the years. Groundbreaking success  was recently achieved through the introduction of checkpoint blockade which  releases T-cells from the physiological negative feedback mechanisms exploited  by tumors to escape immune attack. Blockade of inhibitory receptors such as  CTLA-4 and PD-1 expressed on activated T-cells has seen survival of some stage  IV melanoma patients dramatically increased. However, it remains the case that  not all patients respond, but all may suffer side effects.

Further improvements  of today’s treatment strategies is still urgently required.In the present  proposal, we focus on the numerically minor subset of γδ T-cells, which has a  major role in defense against microbial and non-microbial challenges but has  been under-investigated in the context of checkpoint blockade in cancer. Results  from in vitro and in vivo experiments suggest that these unique T-cells sense  infected and/or malignant cells, contribute efficiently to the regulation of  immunity and thus to the elimination of these cells. Little is known about the  structures which are recognized by γδ T-cells in an MHC-independent manner.  Peripheral blood γδ T-cells consist usually of a majority carrying the Vδ2-TCR  and a minority of cells expressing Vδ1- and other Vδ-TCRs. The Vδ2 T-cell subset  is associated with the expression of semi-invariant public TCRs, which recognize  phospho-antigens (pAgs) or pAg-triggered cell surface molecules such as  butyrophilin. In contrast, Vδ1 T-cells are focused on a private repertoire with  a few high frequency clonotypes.The role of both Vδ1 and Vδ2 T-cells in cancer  immunosurveillance is controversial. We and others have reported both, positive  and negative associations of γδ T-cell frequencies with melanoma patient  survival.

Here, we propose a comprehensive analysis of γδ T-cells in stage IV  melanoma patients prior to and under PD-1 blockade to investigate their role in  a) melanoma rejection and b) the potential direct and indirect immunmodulatory  effects of checkpoint blockade (γδ T-cells express checkpoint molecules just as  do T-cells). Deep-phenotyping (using CyTOF), investigation of  (poly)functionality, proliferative capabilities, and γδ TCR-repertoire analysis  of peripheral blood γδ T-cells will be contrasted with investigations of the  presence or absence of γδ T-cell subsets infiltrating the tumor, allowing a  comprehensive interpretation of resulting data combined with clinical meta-data  available for all patients that have been recruited into our biobank.  Additionally, we aim to investigate tumor-specific γδ T-cell clones and their  amplification by “γδ T-cell boosters” in vitro.The environment of FOR2799 will  provide optimal conditions for a sustainable exchange and effective research  strategy targeting exploitation of γδ T-cells in future cancer treatment  regimes.

PD Dr. Kilian Wistuba-Hamprecht

Eberhard Karls University Tübingen
Section for Clinical Bioinformatics, Internal Medicine I
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