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Detecting and targeting tumor relapse by its resistance to innate effectors at early recurrence

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Abstract

Tumor recurrence represents a major clinical challenge. Our data show that emergent recurrent tumors acquire a phenotype radically different from that of their originating primary tumors. This phenotype allows them to evade a host-derived innate immune response elicited by the progression from minimal residual disease (MRD) to actively growing recurrence. Screening for this innate response predicted accurately in which mice recurrence would occur. Premature induction of recurrence resensitized MRD to the primary therapy, suggesting a possible paradigm shift for clinical treatment of dormant disease in which the current expectant approach is replaced with active attempts to uncover MRD before evolution of the escape phenotype is complete. By combining screening with second-line treatments targeting innate insensitivity, up to 100% of mice that would have otherwise relapsed were cured. These data may open new avenues for early detection and appropriately timed, highly targeted treatment of tumor recurrence irrespective of tumor type or frontline treatment.

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Figure 1: Transition from MRD to recurrence is characterized by a local inflammatory response.
Figure 2: Il-6 and Vegf correlate with early tumor progression.
Figure 3: Plasmid assay to detect tumor recurrence.
Figure 4: Premature induction of recurrence resensitizes tumors to frontline therapies.
Figure 5: Recurrent tumors are insensitive to innate immune effectors.
Figure 6: Targeting the recurrence-specific phenotype of innate immune insensitivity.

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Acknowledgements

We thank T. Higgins for expert secretarial assistance and M. Behrens and K. Knutson for help with Her-2-neu mice. This work was supported by the Richard M. Schulze Family Foundation, the Mayo Foundation, Cancer Research UK, US National Institutes of Health grants R01 CA107082, R01CA130878 and R01 CA132734 and a grant from T. and J. Paul.

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T.K. and N.B. designed and performed experiments and wrote the manuscript. R.M.D., O.D., D.R.-K. and J.T. designed and performed experiments. J.P., D.M., R.K. and M.C. designed the experiments, analyzed the results and interpreted the data. H.P., A.M., K.H. and P.S. designed the experiments, analyzed the results, interpreted the data and wrote the manuscript. R.V. designed and performed experiments, analyzed the results, interpreted the data and wrote the manuscript.

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Correspondence to Richard Vile.

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Kottke, T., Boisgerault, N., Diaz, R. et al. Detecting and targeting tumor relapse by its resistance to innate effectors at early recurrence. Nat Med 19, 1625–1631 (2013). https://doi.org/10.1038/nm.3397

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