Homocitrullinated cytokeratin 8 (HC-CK8)

Homocitrullinated cytokeratin 8 (HC-CK8) is a post-translationally modified protein formed by the carbamylation of lysine residues in cytokeratin 8, a process typically triggered by inflammation and cellular stress (Cook et al., 2021). In the tumor microenvironment, this modification is mediated by myeloperoxidase (MPO) secreted by myeloid-derived suppressor cells (MDSCs), which converts thiocyanate to cyanate, leading to the homocitrullination of intracellular proteins (Scancell, 2022). These modified proteins are subsequently degraded and presented as neoantigens on MHC class II molecules, specifically HLA-DR4 and HLA-DP4, where they can be recognized by CD4+ T cells (Cook et al., 2021). HC-CK8 is a primary target for Scancell's Moditope platform, particularly the Modi-2 vaccine candidate, which aims to harness cytotoxic CD4+ T cells to selectively eliminate cancer cells (Trinity Delta, 2022). Beyond its role in oncology, HC-CK8 is a significant autoantigen in rheumatoid arthritis, and the presence of anti-homocitrullinated protein antibodies (AHPAs) is a key diagnostic feature of the disease (Choudhury et al., 2023). The therapeutic targeting of HC-CK8 offers a unique strategy to exploit the metabolic stress of tumors, although it requires careful management of potential autoimmune side effects (Scancell, 2022). Clinical development of vaccines targeting HC-CK8 focuses on hard-to-treat solid tumors such as triple-negative breast cancer and ovarian cancer (ClinicalTrials.gov, 2022). Overall, HC-CK8 represents a promising stress-induced post-translational modification (siPTM) target that bridges the gap between immunology and tumor metabolism (Cook et al., 2021).

Other names

Homocitrullinated keratin 8Carbamylated cytokeratin 8Hcit-CK8Hcit-KRT8Carbamylated keratin 8Homocitrullinated Cyk8

Vaccine-mediated induction of cytotoxic CD4+ T-cell responses targeting homocitrullinated epitopes presented on MHC class II molecules.