Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells

Identifying tumor-associated T cell epitopes can be laborious. Robbins et al. now report that they used whole-exome sequence data to identify mutated peptides from tumor antigens that are recognized by tumor-infiltrating T cells from patients with melanoma who experienced therapy-associated tumor regressions. The method will contribute to the identification of new tumor-specific epitopes that may further the development of effective T cell therapies for the treatment of patients with melanoma as well as a variety of additional malignancies. Substantial regressions of metastatic lesions have been observed in up to 70% of patients with melanoma who received adoptively transferred autologous tumor-infiltrating lymphocytes (TILs) in phase 2 clinical trials1,2. In addition, 40% of patients treated in a recent trial experienced complete regressions of all measurable lesions for at least 5 years following TIL treatment3. To evaluate the potential association between the ability of TILs to mediate durable regressions and their ability to recognize potent antigens that presumably include mutated gene products, we developed a new screening approach involving mining whole-exome sequence data to identify mutated proteins expressed in patient tumors. We then synthesized and evaluated candidate mutated T cell epitopes that were identified using a major histocompatibility complex–binding algorithm4 for recognition by TILs. Using this approach, we identified mutated antigens expressed on autologous tumor cells that were recognized by three bulk TIL lines from three individuals with melanoma that were associated with objective tumor regressions following adoptive transfer. This simplified approach for identifying mutated antigens recognized by T cells avoids the need to generate and laboriously screen cDNA libraries from tumors and may represent a generally applicable method for identifying mutated antigens expressed in a variety of tumor types.