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

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 T cells. Instead, the scarcity of interactions between two relatively rare populations – DTCs and endogenous antigen-specific T cells – underlies DTC persistence. This scarcity is overcome by any one of three immunotherapies that increase the number of tumor-specific T cells: T cell-based vaccination, or adoptive transfer of T cell receptor- or chimeric antigen receptor- T cells. Each approach achieves robust DTC elimination, motivating discovery of MHC-restricted and -unrestricted DTC antigens that can be targeted with T cell-based immunotherapies to eliminate the reservoir of metastasis-initiating cells in patients. To investigate the immuno-evasive properties of dormant DTCs in the lung, we inoculated WT Balb/c mice and T cell deficient athymic nude mice with either the metastatic D2A1 cell line or the dormant D2.0R cell line via tail vein injection. Four weeks after tumor cell injection, tumor cells were FACS purified from the lungs or harvested from in vitro culture to identify differentially expressed genes in metastatic compared to dormant cells, and immune competent compared to immunocomprimised hosts.