DNA barcoding reveals ongoing immunoediting of clonal cancer populations during metastatic progression and in response to immunotherapy

Abstract

Cancers evade the immune system in order to grow or metastasise through the process of cancer immunoediting. While immune checkpoint inhibitors have been effective for reactivating tumour immunity in some types of cancer, many other solid cancers, including breast cancer, remain largely non-responsive. Understanding the way non-responsive cancers evolve to evade immunity, what resistance pathways are activated and whether this occurs at the clonal level will improve immunotherapeutic design. We tracked cancer cell clones during the immunoediting process and determined clonal transcriptional profiles that allow immune evasion in murine mammary tumour growth in response to immunotherapy with anti-PD1 and anti-CTLA4. Clonal diversity was significantly restricted by immunotherapy treatment in both primary tumours and metastases. These findings demonstrate that immunoediting selects for pre-existing breast cancer cell populations and that immunoediting is not static, it is ongoing during metastasis and immunotherapy treatment. Isolation of immunotherapy resistant clones revealed unique and overlapping transcriptional signatures. The overlapping gene signature was associated with poor survival of basal-like breast cancer patients in two cohorts. At least one of these overlapping genes has an existing small molecule that can potentially be used to improve immunotherapy response.