Antigenic drift as a mechanism for tumor evasion of destruction by cytolytic T lymphocytes
Xue-Feng Bai, Jinqing Liu, Ou Li, Pan Zheng, Yang Liu
Xue-Feng Bai, Jinqing Liu, Ou Li, Pan Zheng, Yang Liu
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Article Oncology

Antigenic drift as a mechanism for tumor evasion of destruction by cytolytic T lymphocytes

Abstract

It is established that mutations in viral antigenic epitopes, or antigenic drifts, allow viruses to escape recognition by both Ab’s and T lymphocytes. It is unclear, however, whether tumor cells can escape immune recognition via antigenic drift. Here we show that adoptive therapy with both monoclonal and polyclonal transgenic CTLs, specific for a natural tumor antigen, P1A, selects for multiple mutations in the P1A antigenic epitope. These mutations severely diminish T cell recognition of the tumor antigen by a variety of mechanisms, including modulation of MHC:peptide interaction and TCR binding to MHC:peptide complex. These results provide the first evidence for tumor evasion of T cell recognition by antigenic drift, and thus have important implications for the strategy of tumor immunotherapy.

Authors

Xue-Feng Bai, Jinqing Liu, Ou Li, Pan Zheng, Yang Liu

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Tumors that recurred after TCRα transgenic T cell (TCRαTg) therapy harbo...
Tumors that recurred after TCRα transgenic T cell (TCRαTg) therapy harbored multiple mutations in the P1A epitope. P1A gene fragments were amplified from recurrent tumors and analyzed by either restriction enzyme mapping or by cloning followed by sequencing. (a) Restriction mapping by a panel of restriction enzymes that identify mutations P1A(1P) and P1A(7P) (HaeIII), P1A(6R) (Fnu4HI), and any alteration in nucleotides encoding P8 and P9 (BbsI). P1A fragments were amplified from tumor cells from mice that received TCRαTG wild-type T cell treatment (Ntg). Note the presence of mutation P1A(6R) and alterations in P8 or P9 in the TCR α chain–transgenic group, but not in the nontransgenic group. Similar results were observed in another recurrent tumor from mice that received transgenic T cells (data not shown). (b) Sequencing of the P1A fragment that resisted digestion by BbsI. Note that of the three clones analyzed, two had mutation P1A(8G) and one had mutation P1A(8L).