Escape from Innate Immune Effectors Is Necessary for Tumor Recurrence

Dormant tumors often persist as undetectable minimal residual disease (MRD) for long periods prior to tumor recurrence, underscoring the importance of developing screening methods that identify occult MRD and predict tumor relapse. Moreover, it is unclear what phenotypic properties facilitate the emergence of tumor cells from dormant MRD. Kottke and colleagues found that the transition of tumor cells out of MRD into actively proliferating recurrent tumors was associated with induction of a local, host-derived innate immune response in several murine tumor models. This response was characterized by expression of proinflammatory cytokines, including interleukin (IL)-6 and VEGF, similar to the host response to infection, and could be detected by measuring serum IL-6 and VEGF levels in mice harboring small, emerging tumors but not those with established recurrent tumors, suggesting that this innate immune response correlates with early tumor progression. Indeed, elevated serum VEGF or activation of a VEGF promoter–driven luciferase reporter was predictive of tumor recurrence. In addition to acquired treatment-specific resistance, recurrent tumors that expanded from MRD also exhibited a complete loss of sensitivity to innate immune effectors, in particular natural killer (NK) cells and IFN-α, indicating that evasion of this inflammatory response is necessary for tumor outgrowth. Intriguingly, VEGF administration during MRD prior to innate immune escape stimulated premature tumor recurrence and enhanced the sensitivity of recurrent tumors to initial therapy, resulting in more effective tumor clearance and prolonged survival. Furthermore, recurrent tumors were effectively targeted by second-line treatments specific to their innate immune-insensitive phenotype, such as oncolytic virotherapy, whereas early IFN-α treatment was effective against MRD. These findings support development of screening methods for early detection of occult MRD and suggest that promoting recurrence, rather than passive waiting, may identify MRD and enable elimination of dormant tumors.

Kottke T, Boisgerault N, Diaz RM, Donnelly O, Rommelfanger-Konkol D, Pulido J, et al. Detecting and targeting tumor relapse by its resistance to innate effectors at early recurrence. Nat Med 2013;19:1625–31.

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