Abstract
The vertebrate immune system has evolved to protect against infections that threaten survival before reproduction. Clinically manifest tumours mostly arise after the reproductive years and somatic mutations allow even otherwise antigenic tumours to evade the attention of the immune system1,2,3. Moreover, the lack of immunological co-stimulatory molecules on solid tumours could result in T-cell tolerance4,5,6,7,8; that is, the failure of T cells to respond. However, this may not generally apply9,10. Here we report several important findings regarding the immune response to tumours, on the basis of studies of several tumour types. First, tumour-specific induction of protective cytotoxic T cells (CTLs) depends on sufficient tumour cells reaching secondary lymphatic organs early and for a long enough duration. Second, diffusely invading systemic tumours delete CTLs. Third, tumours that stay strictly outside secondary lymphatic organs, or that are within these organs but separated from T cells by barriers, are ignored by T cells but do not delete them. Fourth, co-stimulatory molecules on tumour cells do not influence CTL priming but enhance primed CTL responses in peripheral solid tumours. Last, cross priming of CTLs by tumour antigens, mediated by major histocompatibility complex (MHC) class I molecules of antigen-presenting host cells, is inefficient and not protective. These rules of T-cell induction and maintenance not only change previous views but also rationales for anti-tumour immunotherapy1,2.
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Acknowledgements
We thank K. McCoy for critical review of the manuscript and N. Wey for photographs. This work was funded by grants from the Swiss National Science Foundation (to R.M.Z) and the Kanton Zurich.
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Figure 1
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Comparison of tumor take versus induction of anti-tumor CTL responses after transplantation of minor histo-incompatible tumor fragments.
MC-GP tumor pieces were transplanted into both flanks of C57BL/10 mice. Tumor growth (A) and secondary CTL activity (B) are presented as either growing (s) or rejected (t) tumors, according to the results. The numbers of growing or rejected tumors over the total number of transferred tumor pieces or cell suspensions is indicated in A. GP-33-specific CTL responses were assessed by a 51Cr-release assay after 5 days in vitro restimulation of spleen cells taken 40 days after transplantation of the tumor fragment. CTL activity is given for each group as mean + SD. These results thus demonstrate that growing tumor pieces did not induce a GP33-specific CTL response (B), indicating that strictly peripheral antigens did not induce CTLs even in a situation where minor histoincompatibility antigens may have provided additional CTL-epitopes and/or T help.
Figure 1
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Immunogenicity of MC-GP versus MC-GP-B7 cells.
(A) We compared the rejection kinetics of H8 splenocytes (GP33-tg H8 mice on the C57BL/6 background 1) expressing the CTL epitope GP33 after priming of C57BL/6 mice with MC-GP and MC-GP-B7 tumor cells in vivo. GP33-transgenic H8 and C57BL/6 control splenocytes were CFSE labeled and 2x107 splenocytes of each were transferred to C57BL/6 mice that had been primed 8 days previously with either 2x106 live MC-GP or MC-GP-B7 cells intraperitoneally. G33-41 expressing splenocytes were labeled with a high intensity of CFSE (5- and 6-carboxyfluorescein diacetate succinimidyl ester, Molecular Probes, Eugene, OR, USA) fluorescence, whereas C57BL/6 splenocytes were labeled with a low intensity of CFSE fluorescence. Mice primed with MC-GP or with MC-GP-B7 cells similarly rejected transfused GP33-expressing H8-splenocytes by 48 hours after transfer. The percentage specific rejection was calculated as described 2. A LCMV day 60 immune mouse was used as positive control. (B) In addition, we also analyzed the stimulatory capacity of GP-expressing tumor cells with or without co-expression of B7 by assessing specific CD8+ T cell expansion after priming with MC-GP or MC-GP-B7 tumor cells. 2x106 splenocytes from a Db plus GP33-specific TCR transgenic mouse (318 mouse 3) were transferred into syngeneic C57BL/6 mice that were additionally treated with 2x106 MC-GP or MC-GP-B7 tumor cells i.p.. The transferred 318 cells were followed by monitoring Vb8.2 (Vb8.2-FITC), Va2 (anti-Va2-PE) and CD8+ (anti-CD8-TRI). A comparable 10-20 fold expansion (14.1+6.3x for MC-GP and 12.8+5.4x for MC-GP-B7) of transferred 318 cells was observed; the kinetics were comparable at 8-12 days after immunization with either tumor cell line. As a positive control LCMV infection caused about a 60-fold (57.2+9.6) expansion (Fig. 4B6). Results are shown as mean + SD of 3 to 4 animals per group. Experiments were repeated twice with similar results.
Together, these results indicate a similar immunogenicity of B7+ and B7- MC-GP cells when assessed in sensitive in vivo readouts.
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Ochsenbein, A., Sierro, S., Odermatt, B. et al. Roles of tumour localization, second signals and cross priming in cytotoxic T-cell induction. Nature 411, 1058–1064 (2001). https://doi.org/10.1038/35082583
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DOI: https://doi.org/10.1038/35082583
