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

Paul F Robbins, Yong-Chen Lu, Mona El-Gamil, Yong F Li, Colin Gross, Jared Gartner, Jimmy C Lin, Jamie K Teer, Paul Cliften, Eric Tycksen, Yardena Samuels & Steven A Rosenberg

Nature Medicine 19, 747–752 (2013)

Editor's comments:
Which antigens facilitate tumor rejection during successful immunotherapy The successful outcome of an immunotherapy is associated with the infiltration of tumor-specific T-killer lymphocytes in the tumor tissue. These lymphocytes are able to detect various antigens presented in the HLA class I molecules including melanocytic differentiation antigens, cancer/testis antigens and other antigens. Robbins PF and Rosenberg SA and colleagues have developed a new screening approach that allows to find mutated proteins of individual tumor cells. The respective T-cell epitopes were synthesized. The authors have elegantly shown that private mutations in the tumor cells are strong antigens that facilitate tumor rejection by adoptive T-cell transfer.

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 trials. In addition, 40% of patients treated in a recent trial experienced complete regressions of all measurable lesions for at least 5 years following TIL treatment. 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.