073 Characteristics of DFSP tumors in adenosine deaminase deficient-severe combined immunodeficiency (ADA-SCID)

Abstract

Cancer immunotherapies with monoclonal antibodies (mAb) against exhaustion-associated surface molecules, known as immune-checkpoints, reactivate T cells cytotoxic for cancers, and significantly improve survival of patients with various types of cancer. These immunecheckpoint inhibitors are directed against cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1), and disruption of their interactions improves the intermediate-term prognosis even in patients with advanced stage IV melanoma. As the immune system is able to kill tumor cells, it is not astonishing that cancer cell killing has also been demonstrated during immune checkpoint inhibitor therapies. Preclinical data, however, has shown that anti-cancer immunity is not limited to killing cancer cells, and other mechanisms, such as permanent growth arrest or cellular senescence may play an important role as well. Here, we first show that treatment of humans with immune-checkpoint inhibitors induced, besides killing, interferon-dominated type I immunity and senescence in regressing melanoma metastases. To investigate the underlying mechanisms in more detail, we analyzed immune checkpoint inhibitors in advanced solid cancers of RIP1-Tag2 mice, expressing large T antigen (Tag) under the insulin promoter. Besides partial killing of tumor cells, therapy with immune-checkpoint inhibitors induced type I immunity, a p16 INK4a+ /Ki67senescent phenotype in the remaining cancer cells, and restored long-term survival. In clear contrast, cancers of RIP1-Tag2xSTAT1-/mice, deficient in interferon-gsignaling, were resistant to interferon-induced senescence, both in vitro and in vivo. As a consequence, therapy of STAT1-deficient cancers with immune-checkpoint inhibitors in RIP1-Tag2xSTAT1-/mice completely failed. Thus, cancer control by immunotherapy with immune-checkpoint inhibitors strictly requires Stat1-dependent cancer cell senescence.