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* Fred Hutchinson Cancer Research Center, Seattle, WA 98109;
Division of Oncology, Department of Medicine, University of Washington, Seattle, WA 98195;
Department of Immunology, University of Washington, Seattle, WA 98195; and
City of Hope National Medical Center and Beckman Research Institute, Duarte, CA 91010
We have targeted CD22 as a novel tumor-associated Ag for recognition by human CTL genetically modified to express chimeric TCR (cTCR) recognizing this surface molecule. CD22-specific cTCR targeting different epitopes of the CD22 molecule promoted efficient lysis of target cells expressing high levels of CD22 with a maximum lytic potential that appeared to decrease as the distance of the target epitope from the target cell membrane increased. Targeting membrane-distal CD22 epitopes with cTCR+ CTL revealed defects in both degranulation and lytic granule targeting. CD22-specific cTCR+ CTL exhibited lower levels of maximum lysis and lower Ag sensitivity than CTL targeting CD20, which has a shorter extracellular domain than CD22. This diminished sensitivity was not a result of reduced avidity of Ag engagement, but instead reflected weaker signaling per triggered cTCR molecule when targeting membrane-distal epitopes of CD22. Both of these parameters were restored by targeting a ligand expressing the same epitope, but constructed as a truncated CD22 molecule to approximate the length of a TCR:peptide-MHC complex. The reduced sensitivity of CD22-specific cTCR+ CTL for Ag-induced triggering of effector functions has potential therapeutic applications, because such cells selectively lysed B cell lymphoma lines expressing high levels of CD22, but demonstrated minimal activity against autologous normal B cells, which express lower levels of CD22. Thus, our results demonstrate that cTCR signal strength, and consequently Ag sensitivity, can be modulated by differential choice of target epitopes with respect to distance from the cell membrane, allowing discrimination between targets with disparate Ag density.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This research was supported by National Institutes of Health Grants R21 CA117131 (to O.W.P.), R01 CA76287 (to O.W.P.), CA18029 (to P.D.G.), and CA33084 (to P.D.G.); Lymphoma Research Foundation Grant MCLI-07-012; and gifts from Mary and Geary Britton-Simmons, David and Patricia Giuliani, the Hext Family Foundation, and James and Sherry Raisbeck (to O.W.P.). S.E.J. is supported by a stipend from the National Institutes of Health Medical Scientist Training Program, a Poncin Award, and an Academic Rewards for College Scientists Award.
2 Address correspondence and reprint requests to Dr. Oliver W. Press, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109. E-mail address: press{at}u.washington.edu
3 Abbreviations used in this paper: scFv, single-chain (fraction-variable) Ab; 7-AAD, 7-aminoactinomycin D; ABS, antibody binding sites; BLT, N-
-benzyloxycarbonyl-L-lysine thiobenzyl ester; cTCR, chimeric TCR; MFI, mean fluorescence intensity; PEG, polyethylene glycol; pMHC, peptide-MHC; WT, wild type.
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