Cathepsin B Cleavage of KRas G12/G13 Neoepitopes May Drive Immune Evasion in Tumors

Activating mutations in KRas, NRas, and HRas are prevalent in over 25% of all tumors, with G12 or G13 mutations being predominant. While small molecule inhibitors show promise for KRas-mutated tumors, immunotherapy has largely failed in clinical settings, despite some vaccine-induced responses. Inflammation is a known precursor for many KRas-associated tumors, where lysosomal enzyme cathepsin B leaks into the cytoplasm. This enzyme, typically an exopeptidase, gains endopeptidase activity at higher cytoplasmic pH and is consistently upregulated in tumors, contributing to tumorigenesis through mechanisms like apoptosis and extracellular matrix digestion. This paper explores its potential role in immune evasion.

Researchers investigated the potential role of cathepsin B in the immune evasion of KRas-mutated tumors. They specifically examined the predicted effect of cathepsin B on KRas neoepitopes, focusing on G12 and G13 mutant peptides. The study involved predicting how cathepsin B cleavage patterns might destroy these neoepitopes, thereby preventing their binding to MHC I molecules. Additionally, they reviewed existing literature on the interaction of cathepsin B with trypsinogen in the pancreas and caspases in inflammasomes, considering the implications of premature trypsin activation on immune evasion, particularly for G12R mutants. The findings were summarized in a schematic model.

The study predicts that cathepsin B cleavage patterns could lead to the destruction of KRas G12 and G13 mutant neoepitope peptides. This destruction would prevent these peptides from binding to MHC I molecules, effectively rendering them immunologically invisible to the immune system. This mechanism offers a novel explanation for the observed resistance of KRas-mutated tumors to immunotherapy. The review also highlighted interactions of cathepsin B with other key inflammatory and proteolytic enzymes. Specifically, reports on cathepsin B's interaction with trypsinogen in the pancreas and caspases within inflammasomes were examined. The authors further considered the potential impact of premature trypsin activation on the immune evasion of G12R mutants, suggesting a broader proteolytic network contributing to immune escape. Their observations and literature review culminated in a schematic model illustrating the complex interplay between inflammation, cathepsin B, trypsin, and caspases in facilitating KRas and related Ras family gene product immune evasion. This model posits that cathepsin B's altered activity in inflammatory tumor microenvironments directly undermines the presentation of crucial tumor antigens.

Cathepsin B cleavage patterns of KRas may lead to the destruction of the G12 and G13 mutant neoepitope peptides that would otherwise bind to MHC I, thereby rendering them immunologically invisible.