Antigenic drift as a mechanism for tumor evasion of destruction by cytolytic T lymphocytes
Xue-Feng Bai, … , Pan Zheng, Yang Liu
Xue-Feng Bai, … , Pan Zheng, Yang Liu
Published May 15, 2003
Citation Information: J Clin Invest. 2003;111(10):1487-1496. https://doi.org/10.1172/JCI17656.
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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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Figure 1

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Adoptive therapy with P1A-specific transgenic T cells selects for T cell...
Adoptive therapy with P1A-specific transgenic T cells selects for T cell–resistant tumor cells. (a) Treatment of large P1A-expressing tumors with transgenic T cells results in rapid shrinkage of tumors, followed by stagnation and resurgence of tumor growth. J558-Neo tumor cells (5 × 106) were injected subcutaneously into RAG-2–/– BALB/c mice. Two to three weeks later, when the tumors reached 1.2–1.4 cm in diameter, purified transgenic T cells (5 × 106/mouse) were injected intravenously. The treatment was repeated on day 31 when the tumors had returned to their pretreatment size, as indicated by arrows. Mice were euthanized on day 39 (n = 4). (b) Tumor cells isolated after two treatments were resistant to cytolysis by activated P1A-specific T cells. Tumor cells were isolated from two different mice and were compared with their parental tumor J558-Neo cells for their susceptibility to cytolysis in a 6-hour cytotoxicity assay. Data shown are representative two experiments. A, AvaII; F, Fnu4HI; U, uncut. (c) Expression of P1A was not lost in the P1CTL-resistant tumor cells. First-strand DNA was generated from total RNA using reverse transcriptase and amplified with primers specific for either GAPDH (700-bp product) or P1A (500-bp product). (d) Normal expression of H-2Ld on the surface of CTL-resistant tumor cells. Histograms depict binding of second-step reagent (dotted lines) or H-2Ld–specific mAb followed by the second-step reagent (solid lines). E/T, effector to target ratio.