Host-protective anti-tumor immune responses induce immunoediting of indolent but not quiescent dormant tumor cells

Abstract

Abstract Two major barriers to cancer immunotherapy include tumor-induced immune suppression mediated by myeloid-derived suppressor cells (MDSCs), and poor immunogenicity of the tumor expressing self-antigens. To overcome these barriers, we used adoptive immunotherapy (AIT) by means of tumor-sensitized T cells and CD25+ NKT cells combined with Decitabine (Dec). Dec enhanced immunogenicity of the tumor, and the presence of CD25+ NKT cells rendered T cells resistant to remaining MDSCs. This combinatorial therapy significantly prolonged survival of animals bearing metastatic tumor cells. However, AIT eventually induced tumor immunoediting and subsequent tumor escape and progression. We hypothesized that conventional cancer therapeutics result in residual dormant tumor cells with a heterogeneous sensitivity to immunoediting; we therefore sought to identify the characteristics of dormant tumor cells that are resistant to immunoediting. We used Adriamycin (ADR) chemotherapy or radiation therapy (RT) which simultaneously induces tumor cell death and tumor dormancy. Resultant dormant cells became refractory to additional doses of ADR or RT, but they remained sensitive to tumor-reactive immune cells. Importantly, we discovered that dormant tumor cells contained indolent cells that expressed low levels of Ki67 (Ki67+/low) and quiescent cells that were Ki67 negative (Ki67−). Whereas the former were prone to tumor immunoediting and escape, the latter did not demonstrate immunoediting. Our results suggest that administration of immunotherapy during quiescent tumor dormancy could overcome tumor relapse and prevent disease progression to advanced stage cancer.