Domínios glicosilados de mucinas como estratégias inovadoras e alternativas de modelação do sistema imunitário

Immunotherapeutic strategies are currently used for treating cancer and autoimmune diseases [1,2]. While these strategies hold immense promise, there’s a delicate balance between immunity and tolerance to strike. Moreover, not all patients respond, and therapy resistance may occur, leaving a critical need for novel immunomodulatory approaches. MUC4Health addresses the need of innovative immunomodulatory strategies, considering the mucin glycocode (glycosylation of proteins) as immune checkpoints for enhancing anti-tumor immunity and controlling auto immune diseases[4,5]. A hallmark feature of cancer is the chemical alteration of the mucin glycocode [6] (Fig 2A). Glycosylation of mucins is controlled by the concerted action of highly “specialized” enzymes (GTs) (Fig 2B). In cancer, changes in expression, location and/or activity of GTs yield the generation of tumor-associated mucin glycoepitopes (Fig 2C). These new glycoepitopes are recognized by immune-receptor lectins, namely MGL and Siglecs, that often promote immune suppression [4] (Fig 3). MUC4Health targets the tumor-associated mucin glycocode/immune lectins interaction axis as a key immune checkpoint with the major goal to potentially develop the next generation of immunomodulators to address the delicate balance between tolerance and immunity. To achieve our goal, MUC4health has two specific aims: 1. To engineer, using precise chemoenzymatic synthesis, homogeneous well-defined mucin glycodomains: By controlling the action of specific GTs we will break the limits on chemoenzymatic synthesis by generating tumor-associated mucin glycodomains with an unprecedent chemical diversity (size, peptide sequence, glycan density and diversity). 2. To control the balance between the blocking versus signal induction capacity of mucin glycodomains. The molecular and cellular mechanisms of tumor-associated mucin glycocode recognition by key immune lectins will be deciphered, providing an unprecedented structure-immune relationship data. On this basis, MUC4Health aims at modulating lectin-mediated immune responses by chemically adjusting the size, peptide sequence and the chemical diversity & density of the glycans on the mucin glycodomains (Fig 4). Hence, MUC4Health will generate: 1) Small mucin glycodomains, which are expected to penetrate better in the tumor microenvironment than antibodies, acting as antagonists, blocking lectin-mediated suppression. This is beneficial to combat cancer since tolerance is alleviated and anti-tumor immunity is promoted. 2) Large mucin glycodomains, with multiple tandem repeated domains to mimic the tumor-associated presentation, to act as agonists, inducing signaling and providing tolerance. This effect counteracts unwanted or exacerbated immune reactions and restores tolerance in case of autoimmunity. To complete its ground-breaking objectives the team of MUC4Health will synergistically combine precise chemoenzymatic methods and molecular biology, with glycomics (glycan microarrays and MS) and biophysical and structural techniques, NMR assisted by molecular modelling, with immunological assays. From this bottom to top approach, from chemistry to immunology, MUC4Health will potentially yield novel therapeutic immunomodulatory strategies.