Highlights in Cancer Research: January 2023

The development of novel immunotherapies is limited by the availability of tumor-specific antigens. Mutant oncoproteins are amongst the most attractive targets as they are inherently tumor-specific, but these proteins are often intracellular and not accessible to protein- or cell-based therapies. Nature solves this problem with the native antigen presentation pathway, which uses MHC I molecules to bring intracellular protein fragments to the cell surface for T cell recognition. Immunotherapies targeting oncoprotein-derived MHC I complexes have emerged as a promising new avenue for expanding the scope of targetable tumor-specific antigens. In this Cancer Cell paper, Zhang et al. expand further upon this approach by demonstrating that KRas G12C proteins treated with covalent inhibitors can be processed through the antigen presentation pathway, resulting in the presentation of MHC I complexes containing inhibitor-modified KRas G12 peptides. These inhibitor-modified MHC I complexes represent a new class of tumor-specific antigens, requiring both a mutant oncoprotein (KRas G12C) and the presence of a covalent inhibitor for generation of the target antigen. The authors were able to identify antibodies specific to inhibitor-modified MHC I complexes containing the preclinical KRas G12C inhibitor ARS1620 and the FDA-approved inhibitor Sotorasib. Using a bispecific T-cell engager derived from an inhibitor-specific antibody, the authors show that these MHC I complexes can be targeted for immunotherapy, offering superior efficacy to treatment with the covalent inhibitor alone. The authors demonstrate that covalent inhibitors can serve to potentiate immunotherapy, offering the potential for synergistic approaches leveraging the distinct modalities of both small molecule inhibitors and protein-based immunotherapies.