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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In adoptive therapy, TCR α chain–transgenic T cells mounted a robust CTL...
In adoptive therapy, TCR α chain–transgenic T cells mounted a robust CTL response against the P1A35-43 epitope presented by H-2Ld and caused transient rejection of large established tumors. (a) Expression of P1CTL TCR α chain on more than 90% of T cells, as revealed by coexpression of the transgenic Vα8 chain and CD3 or CD8. A significant (although small) proportion of CD8 T cells reacted specifically to H-2Ld:P1A complex. (b) Adoptive transfer therapy of mice with large tumor burdens using spleen cells from either TCR α chain–transgenic mice or their wild-type, nontransgenic (Ntg) littermates. RAG-2–/– BALB/c mice were transplanted with 5 × 106 J558-Neo tumor cells. Once tumors were greater than 1.5 cm in diameter, unprimed spleen cells from either wild-type or transgenic littermates were injected intravenously. Tumor growth was monitored with calipers. Data show average tumor diameter of five mice per group. †The time of sacrifice. **Significantly different from nontransgenic (P ≤ 0.01) as determined by Student t test. (c) Robust CTL response in mice that received transgenic T cells. At 4–5 weeks after adoptive transfer, spleen cells of recipient mice were stained with anti-CD8 in conjunction with H-2Ld loaded with either control or P1A peptides. Three independent experiments revealed that 10–70% of CD8 T cells were capable of binding the H-2Ld:P1A complex.