Vitamin A or retinol is essential in embryonic development, the visual cycle and the immune system. Vitamin A is converted to retinoic acid (RA) by aldehyde dehydrogenases (ALDHs). The family of... Show moreVitamin A or retinol is essential in embryonic development, the visual cycle and the immune system. Vitamin A is converted to retinoic acid (RA) by aldehyde dehydrogenases (ALDHs). The family of ALDHs consists of 19 members, three of which (ALDH1A1, ALDH1A2 andALDH1A3) have retinal as their preferred substrate. Due to a lack of selective and potent inhibitors for these enzymes, it is difficult to study their individual contribution to Vitamin A metabolism in biological systems.Therefore an activity-based probe based on the chemical structure of retinal has been synthesized to enable activity-based protein profiling (ABPP) of ALDHs. The probe covalently binds to the catalytic cysteine of ALDH enzymes which can then be visualized on gel or analyzed by proteomics using ligation chemistry.After biological evaluation of the probe this chemical tool has been used to study the influence of individual ALDH enzymes on the mucosal immune system and to determine the ALDH profile of several breast cancer cell lines. Thus showcasing its use to study Vitamin A metabolism in a wide variety of biological settings including but not limited to: immunology, cancer and (cancer) stem cells. Show less
MHC class I antigen-presentation plays a pivotal role in anti-tumor immunity. High surface expression of MHC-I molecules is generally correlated with high CD8 T cell infiltrate and improved overall... Show moreMHC class I antigen-presentation plays a pivotal role in anti-tumor immunity. High surface expression of MHC-I molecules is generally correlated with high CD8 T cell infiltrate and improved overall survival in many cancers. In contrast, partial or complete loss of MHC-I surface expression is associated with reduced survival and primary-resistance to immunotherapy in cancers. Expression of additional molecules in the tumor microenvironment (TME), such as PD-L1 and HLA-E, further shape immune responses. The presence of immune cells and the expression of immune-related genes together determine the ‘immune landscape’ of cancers, while the local production of interferons strongly impacts this environment. Although MHC-I and PD-L1 are both regulated by the IFN pathway, an in-depth study on immune escape of NSCLC showed that the expression of co-inhibitory markers and the loss of MHC-I expression are two independent mechanisms of immune evasion. This classifies tumors into different “types” depending on their MHC-I and PD-L1 expression. The differential expression of MHC-I and PD-L1 suggests that immune-escape of cancer cells occurs through a multitude of distinct “hard-wired” and “soft-wired” modifications and knowing which of the mechanisms underlie immune escape determines which immunotherapeutic strategy has the most potential for clinical success. Show less
