Carbonic anhydrase IX-derived peptide–Major Histocompatibility Complex (CAIX pMHC)

Carbonic anhydrase IX (CAIX) is a transmembrane enzyme that is highly overexpressed in various solid tumors, particularly clear cell renal cell carcinoma, as a result of the hypoxic tumor microenvironment (UniProt: Q16790). The CAIX-derived peptide–MHC complex consists of specific intracellularly processed CAIX fragments presented on the cell surface by Major Histocompatibility Complex (MHC) molecules, such as HLA-A*02:01 (PubMed: 15150597). These complexes serve as specific targets for T-cell receptors (TCRs), which can be utilized in adoptive cell therapies or bispecific T-cell engagers to direct the immune system against malignant cells (PubMed: 31515463). Because CAIX expression is minimal in most healthy tissues but ubiquitous in certain cancers, these pMHC complexes are attractive targets for precision immunotherapy. However, therapeutic development must account for low-level CAIX expression in the gallbladder and stomach to avoid on-target, off-tumor toxicities. Engagement of these complexes by engineered TCRs leads to the formation of an immunological synapse and the release of cytotoxic granules, resulting in tumor cell death.

Other names

CA9 peptide-HLA complexCAIX-HLA-A*02:01 complexCarbonic anhydrase 9 peptide-MHCCAIX pMHC complex

Engagement of the T-cell receptor (TCR) with the CAIX peptide-MHC complex triggers T-cell activation, the formation of an immunological synapse, and subsequent lysis of the target tumor cell through the release of perforin and granzymes.