Impact of targeted alpha therapy on tumor microenvironment

Actual cancer therapies are facing numerous challenges towards tumor cell destruction: hypoxia is a limit to optimal efficacy of external irradiation, and poor tumor vascularisation restrains access to tumor cells for treatment like Immunotherapies. Furthermore, tumor microenvironment (TME) involves immunoregulatory cells and cytokines, which prevent anti-tumoral immune response. Therapeutic combination could be the key to turn these 'cold' TME into 'hot' ones: more vascularised and infiltrated with immune cells. To this end, this PHd project focus on combining Targeted Alpha-Therapy (TAT) and adoptive transfer of T-cells (ACT).This therapeutic combination resulted in a significant tumor growth delay in a multiple myeloma murine model. Based on these results, the aim of this project was to understand the impact of TAT on the 'cold' TME and on ACT efficacy. Although T cells infiltrated the tumor after ACT, only combination with TAT resulted in regulatory CD4 T cell drop and production of IL-2, CCL-5 and IFNg within the tumor. Furthermore, T cells motility was increased on TAT treated tumor. Combining TAT and ACT appears to turn this 'cold' tumor model into a 'hot' one. To allow a follow-up of the TME and its response to immunotherapy without having to sacrifice the mice, various cell tracking method have been developed and compared. Direct labeling methods, consisting in labeling cells before injection, were not found suitable for fast proliferating cells like CD8 T cells. Therefore, potential target for imaging with radiolabeled antibody were investigated. (author)