MHC-restricted fratricide of human lymphocytes expressing survivin-specific transgenic T cell receptors
Matthias Leisegang, Susanne Wilde, Stefani Spranger, Slavoljub Milosevic, Bernhard Frankenberger, Wolfgang Uckert, Dolores J. Schendel
Matthias Leisegang, Susanne Wilde, Stefani Spranger, Slavoljub Milosevic, Bernhard Frankenberger, Wolfgang Uckert, Dolores J. Schendel
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Research Article Oncology

MHC-restricted fratricide of human lymphocytes expressing survivin-specific transgenic T cell receptors

Abstract

The apoptosis inhibitor protein survivin is overexpressed in many tumors, making it a candidate target molecule for various forms of immunotherapy. To explore survivin as a target antigen for adoptive T cell therapy using lymphocytes expressing survivin-specific transgenic T cell receptors (Tg-TCRs), we isolated HLA-A2–allorestricted survivin-specific T cells with high functional avidity. Lymphocytes expressing Tg-TCRs were derived from these T cells and specifically recognized HLA-A2+ survivin+ tumor cells. Surprisingly, HLA-A2+ but not HLA-A2– lymphocytes expressing Tg-TCRs underwent extensive apoptosis over time. This demise was caused by HLA-A2–restricted fratricide that occurred due to survivin expression in lymphocytes, which created ligands for Tg-TCR recognition. Therefore, survivin-specific TCR gene therapy would be limited to application in HLA-A2–mismatched stem cell transplantation. We also noted that lymphocytes that expressed survivin-specific Tg-TCRs killed T cell clones of various specificities derived from HLA-A2+ but not HLA-A2– donors. These results raise a general question regarding the development of cancer vaccines that target proteins that are also expressed in activated lymphocytes, since induction of high-avidity T cells that expand in lymph nodes following vaccination or later accumulate at tumor sites might limit themselves by self-MHC–restricted fratricide while at the same time inadvertently eliminating neighboring T cells of other specificities.

Authors

Matthias Leisegang, Susanne Wilde, Stefani Spranger, Slavoljub Milosevic, Bernhard Frankenberger, Wolfgang Uckert, Dolores J. Schendel

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Figure 4

Cytotoxic activity of survivin-specific TCR-modified PBLs.

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Cytotoxic activity of survivin-specific TCR-modified PBLs. The cytotoxic...
The cytotoxicity of survivin-specific TCR-engineered PBLs using lymphocytes and T cell clones as target cells was determined in a standard 4-hour chromium release assay using varying E/T ratios, and results are presented as percent specific lysis. (A) Unstimulated or PHA- or CD3/CD28-activated lymphocytes of HLA-A2– and HLA-A2+ donors were used as target cells at the given E/T ratios. (B) mRNA levels of survivin and β2-microglobulin (β2m) were analyzed by RT-PCR. (C) HLA-A2+ T cell clones with specificity for the TAA MART-1/melan-A (A42, ref. 28), tyrosinase (Tyr-F8, ref. 29), or Epstein Barr virus (FaLe) were assessed as target cells for TCR-modified effector cells. An alloreactive clone (JB4, ref. 30) derived from an HLA-A2– donor served as a negative control. (D) Corresponding survivin mRNA levels of the T cell clones were determined and depicted as in B. Cytotoxicity data represent means of duplicates measured at each E/T ratio. These data are representative of 2–4 individual donors.