T cells recognize and target somatic mutation–derived epitopes expressed by gastrointestinal tumors.
Major finding: T cells recognize and target somatic mutation–derived epitopes expressed by gastrointestinal tumors.
Clinical relevance: T cells targeting the KRASG12D driver mutation have the potential to treat many tumor types.
Impact: Mutation-specific T cells may allow for personalized therapy targeting immunogenic tumor mutations.
Immunotherapies, including adoptive cell therapy with tumor-infiltrating lymphocytes (TIL) and immune checkpoint inhibition, have proven effective in many tumor types. The clinical activity of these immunotherapies has been suggested to result from T-cell responses against tumor-specific somatic mutation neo-epitopes. However, immune checkpoint blockade is not effective in the majority of gastrointestinal tumors, which have relatively few mutations. Tran and colleagues used next-generation sequencing and high-throughput immunologic screening to show that the majority of patients with metastatic gastrointestinal cancer harbor T cells that recognized specific somatic mutation–derived epitopes expressed on their tumors. TILs were cultured from the patients' metastatic lesions, and a tandem minigene approach was used to test whether the TIL cultures recognized the patient's own tumor mutations. In 9 of 10 patients, CD4+ and/or CD8+ T cells recognized between one and three tumor-specific somatic mutations; however, the same immunogenic epitopes were not identified in multiple patients. The frequency of mutation-reactive TIL cultures derived from metastatic lesions varied but was relatively low, and immunogenic mutations were found in a number of genes implicated in tumorigenesis, including PHLPP1, API5, and H3F3B. Furthermore, CD8+ T cells expressing a HLA-C*8:02–restricted T-cell receptor specifically targeting the KRASG12D driver mutation shared by many tumor types were detected in one patient, suggesting that immunotherapy targeting the KRASG12D epitope could benefit many patients. Together, these findings indicate that many patients with gastrointestinal cancer have immunogenic mutations that are recognized and targeted by T cells. Although additional work is needed to enhance the persistence and potency of adoptively transferred mutation-specific T cells, these data suggest the possibility of developing personalized vaccines and adoptive T-cell therapies targeting tumor-specific immunogenic mutations in patients with gastrointestinal tumors.