The Great Escape

Many tumors exhibit dormancy that can last for years, making the time to clinical recurrence unpredictable. Minimal residual disease (MRD) represents the survival, following therapy, of tumor cells that gives rise to future relapse. A key element of tumor persistence is evasion of immune surveillance. Thus, MRD may be due, at least in part, to acquisition by the tumor of a phenotype that masks it from immune recognition and clearance. Moreover, the phenotype of the recurrent tumor may be radically different from that of the original tumor. The sensitivity of detection of MRD has increased with the advent of methods such as multi-parameter flow cytometry, fluorescence in situ hybridization, and real-time quantitative PCR. MRD is clinically important, as detection augurs a poor prognosis for many types of cancer.

In the current study, Timothy Kottke and colleagues from the Mayo Clinic in Rochester, Minnesota, investigated, using murine models, tumor-antigen expression and cytokine production during progression from MRD to frank relapse. They observed that transition from MRD to proliferating recurrence stimulates an innate immune response; however, the recurrent tumors were found to be insensitive to the immune effectors, a property that enabled them to escape immune clearance. The investigators studied the efficacy of immunotherapy, oncolytic virotherapy, chemotherapy, and T-cell therapy. They observed that proinflammatory cytokines such as IL-6; interferon γ; and serum amyloid P component, a marker of an acute-phase protein response to infection, were associated with emerging recurrence, whereas later and larger, actively growing recurrences exhibited neither proinflammatory cytokines nor the antigens that elicited the immune response. Detection of IL-6 and vascular endothelial growth factor (VEGF) correlated with the onset and early progression of tumor growth in mouse models of melanoma and spontaneous breast cancer. A reporter assay using a luciferase plasmid under control of the VEGF promoter showed a positive signal that was followed by clinical recurrence seven to 12 days later only in the mice that would develop tumors. Kottke and colleagues hypothesized that if the transition from MRD to overt recurrence were induced prematurely, the tumor cells may not have yet acquired the critical properties that allow escape from therapy. In support of this hypothesis, systemic administration of VEGF during MRD led to premature recurrence, with development of angiogenesis and rapid tumor formation, and the induced tumors elicited type I interferon signaling and were susceptible to natural-killer cells and sensitized T cells, features that were no longer present once clinical recurrence was evident.