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Adaptive immunity maintains occult cancer in an equilibrium state

Abstract

The capacity of immunity to control and shape cancer, that is, cancer immunoediting, is the result of three processes1,2,3,4,5,6,7,8 that function either independently or in sequence9: elimination (cancer immunosurveillance, in which immunity functions as an extrinsic tumour suppressor in naive hosts); equilibrium (expansion of transformed cells is held in check by immunity); and escape (tumour cell variants with dampened immunogenicity or the capacity to attenuate immune responses grow into clinically apparent cancers). Extensive experimental support now exists for the elimination and escape processes because immunodeficient mice develop more carcinogen-induced and spontaneous cancers than wild-type mice, and tumour cells from immunodeficient mice are more immunogenic than those from immunocompetent mice. In contrast, the equilibrium process was inferred largely from clinical observations, including reports of transplantation of undetected (occult) cancer from organ donor into immunosuppressed recipients10. Herein we use a mouse model of primary chemical carcinogenesis and demonstrate that equilibrium occurs, is mechanistically distinguishable from elimination and escape, and that neoplastic cells in equilibrium are transformed but proliferate poorly in vivo. We also show that tumour cells in equilibrium are unedited but become edited when they spontaneously escape immune control and grow into clinically apparent tumours. These results reveal that, in addition to destroying tumour cells and sculpting tumour immunogenicity, the immune system of a naive mouse can also restrain cancer growth for extended time periods.

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Figure 1: The adaptive immune system promotes an equilibrium state in primary MCA-induced sarcomas.
Figure 2: Antibody-induced equilibrium disruption does not occur as a result of prolonged de novo transformation.
Figure 3: Demonstration of occult cancer in immunocompetent mice in the equilibrium phase of cancer immunoediting.
Figure 4: Sarcoma cells in equilibrium show high immunogenicity, whereas those spontaneously exiting equilibrium have attenuated immunogenicity.

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Acknowledgements

The authors are grateful for the advice of E. Unanue, G. Dunn, H. Virgin, P. Allen, M. Colonna, J. Trapani, R. Uppaluri, J. Bui and all members of the Schreiber laboratory during the preparation of this manuscript. We also greatly appreciate the technical assistance of C. Arthur, M. White, J. Archambault and J. Sharkey. This work was supported by grants to R.D.S. from the National Cancer Institute, the Ludwig Institute for Cancer Research, the Cancer Research Institute and Atlantic Philanthropies, and to M.J.S. from the National Health and Medical Research Council of Australia for Fellowship and Program Grant Support. C.M.K. was supported by a pre-doctoral training grant from the Cancer Research Institute. J.B.S. was supported by an Australian Postgraduate Research Award.

Author Contributions The work in this paper reflects an equal contribution from the M.J.S and R.D.S. laboratories. C.M.K., M.J.S. and R.D.S. were involved in all aspects of experimental work, project planning and data analysis. W.V. and S.J.R. were responsible for performing and interpreting the histological analyses. L.J.O. and J.B.S. participated in project planning and N.Z. was involved in the experimental work.

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Correspondence to Mark J. Smyth or Robert D. Schreiber.

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Koebel, C., Vermi, W., Swann, J. et al. Adaptive immunity maintains occult cancer in an equilibrium state. Nature 450, 903–907 (2007). https://doi.org/10.1038/nature06309

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