Kurzfassung

T cells can be retrovirally equipped with T cell receptors (TCRs) that are able to recognise tumour-associated antigens (TAA) with high affinity and thereby redirected to kill tumour cells in vitro and in vivo. A heterogenous population of immature or activated myeloid cells (myeloid-derived suppressor cells, MDSC) has emerged as one of the key effector populations of tumour immune escape, which potentially inhibits antitumoural effectiveness of TAA reactive T cells. This project aims to...T cells can be retrovirally equipped with T cell receptors (TCRs) that are able to recognise tumour-associated antigens (TAA) with high affinity and thereby redirected to kill tumour cells in vitro and in vivo. A heterogenous population of immature or activated myeloid cells (myeloid-derived suppressor cells, MDSC) has emerged as one of the key effector populations of tumour immune escape, which potentially inhibits antitumoural effectiveness of TAA reactive T cells. This project aims to improve conventional T cell-based tumour immunotherapy by analysis and suppression of MDSC-mediated tumour immune escape mechanisms. For this purpose, we will use adoptive transfer of T cells redirected with HLA.A*02:01-restricted TCRs of defined specificities (p53(264-272), MDM2(81-88), XBP-1(18-27)) in both a syngeneic mouse tumour model and a NSG-A2 xenograft model. MDSC frequency in the circulation and in the tumour micromilieu as well as MDSC-associated tumour immune escape mechanisms (arginase and downstream products of arginine metabolism, reactive oxygen and nitrogen species) and suppressive properties will be analysed in vitro and in vivo. In parallel, T cell expansion, phenotype and effector functions will be studied and correlated with the MDSC data. MDSC-mediated immunosuppressive pathways will then be specifically targeted by (a) pharmacological inhibitors for arginase (ABH, BEC, nor-NOHA), COX-2 (coxibs) or nitric oxide synthase (L-NMMA), (b) cytokine receptor blocking antibodies, (c) inhibition of the generation or expansion of MDSC (sunitinib, PDE5 inhibitor sildenafil) or (d) maturation / differentiation of MDSC into effective antigen presenting cells (all trans retinoic acid, ATRA). T cell proliferation and effector functions will be further boosted by modulating arginine availability via supplementation of citrulline, a non-toxic precursor amino acid for cellular arginine biosynthesis. In summary, our novel combined approach has the potential to synergistically enhance the efficacy of anti-tumour immunotherapy as a prerequisite for its successful translational implementation in clinical practice as powerful anti-cancer treatment.
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