Editors' ChoiceCancer Immunotherapy

T Cells Take Notice of Distinct Mutations in Cancer Cells

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Science Translational Medicine  05 Jun 2013:
Vol. 5, Issue 188, pp. 188ec92
DOI: 10.1126/scitranslmed.3006619

Antigens are molecular ZIP codes that allow the immune system to sort through and select which cells to ignore and which ones to attack. Change one digit in a ZIP code, and the letter you sent to your aunt in Connecticut could end up with a confused stranger in California. That’s also true for antigens: One amino acid change can make the difference between a cell that is ignored and one that is destroyed. Now, Robbins et al. present new support for the idea that mutations in cancer cells generate new antigens that may be targeted by the immune system.

This study is an in-depth analysis of three patients with melanoma who were successfully treated with a transfusion of T cells harvested from their own tumors. This approach, adoptive cell transfer (ACT) with autologous tumor infiltrating lymphocytes (TILs), has demonstrated durable tumor regressions in some patients. But, what cancer antigen (or antigens) the TILs are (or should be) targeting is an outstanding question in this area. Using whole-exome sequencing to compare tumor and normal tissue for each patient, the investigators identified a panel of distinct cancer-specific mutations for each tumor. Then, using predictive algorithms they narrowed the list from ~300 total mutations to ~50 mutations with features thought to increase their likelihood of being recognized by the immune system, such as major histocompatibility complex (MHC)–binding affinity. Taking this short list of candidates, they tested whether the TILs recognized any of these mutational antigens. In each case, 3 or 4 of these mutations produced new antigens that were recognized by the matching TILs; moreover, recognition of these new antigens persisted in the peripheral blood up to 1 month after ACT therapy.

In concert with other publications, this study supports the concept that cancer-specific mutations can be recognized by the immune system and may be clinically relevant. Recognition of mutational antigens may explain the activity of TIL therapy, although this study lacks direct evidence for a causal relationship, and additional investigation will be necessary. 

P. F. Robbins et al., Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells. Nat. Med., 5 May 2013 (doi: 10.1038/nm.3161). [Full Text]

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