Immune evasion of dormant disseminated tumor cells is due to their scarcity and can be overcome by T cell immunotherapies

Abstract

The period between "successful" treatment of localized breast cancer and the onset of distant metastasis can last many years, representing an unexploited window to eradicate disseminated disease and prevent metastases. We find that the source of recurrence-disseminated tumor cells (DTCs) -evade endogenous immunity directed against tumor neoantigens. Although DTCs downregulate major histocompatibility complex I, this does not preclude recognition by conventional Tcells. Instead, the scarcity of interactions between two relatively rare populations-DTCs and endogenous antigen-specific Tcells-underlies DTC persistence. This scarcity is overcome by any one of three immunotherapies that increase the number of tumor-specific Tcells: Tcell-based vaccination, or adoptive transfer of Tcell receptor or chimeric antigen receptor Tcells. Each approach achieves robust DTC elimination, motivating discovery of MHC-restricted and -unrestricted DTC antigens that can be targeted with Tcell-based immunotherapies to eliminate the reservoir of metastasis-initiating cells in patients.