noCOLDmore · Reprogramming eNdOthelial cells in immune-COLD tuMORs

Линиите свързват координатора с партньорите.

Накратко на български

Цел на проекта

Lung cancer is the leading cause of cancer-related deaths worldwide. Currently, immunotherapy (IT) is the standard of care for the treatment of some subtypes, with only nominal success. IT works best in inflamed “hot” tumors and is often ineffective in immune cell-desert “cold” tumors. In KRAS-mutated lung adenocarcinoma -LUAD, the most frequent type of lung cancer- the presence of a mutation in the STK11/LKB1 gene is linked to a cold tumor, while the co-occurrence of a TP53 mutation corresponds to a hot tumor. Amongst different cell types in the tumor environment impacting immune cell composition, endothelial cells (ECs) present an important and often overlooked modulator of immune profiles. Previous research has identified immunoregulatory genes expressed by ECs and proposed immuno-modulatory roles of ECs. I hypothesize that specific mutations cause the expression of immunosuppressive genes by ECs, which might explain the association of gene mutations affecting the immune environment. Thus, modulating ECs to reprogram them into immunostimulatory phenotypes in the immune cold tumors, could present a promising strategy to improve IT responses. To identify the immunosuppressive gene signature in ECs in immune cold vs hot tumors, I will utilize transgenic mouse models of LUAD: KrasG12D/+; Lkb1flox/flox (KL) and KrasG12D/+; Tp53flox/flox (KP) mice. First, using scRNAseq, I will establish an EC signature linked to the immune cold tumors and subsequently to identify EC-specific candidate immunosuppressive targets. After that, I will use state-of-the-art technologies that enable efficient gene targeting to validate the discovered targets in KL mice. I perform multidisciplinary approaches to delineate the molecular mode of action of the target exhibiting a substantial therapeutic effect in mice and overcoming the resistance to current anti-cancer IT. Finally, I will employ a humanized orthotopic lung PDX mouse model to further validate and test therapeutic opportunities.

Оригинален текст от CORDIS (на английски).

Участници

• VIB VZW · ZWIJNAARDE - GENTКоординаторБелгия
• FUNDACION PARA LA INVESTIGACION BIOMEDICA DEL HOSPITAL UNIVERSITARIO 12 DE OCTUBRE · MadridИспания

Връзки

• Виж в CORDIS
• DOI: 10.3030/101154254
• https://ec.europa.eu/research/participants/documents/downloadPublic?documentIds=080166e520365114&appId=PPGMS