1 2 1 1 2 1 1 068 Stat1-dependent senescence is necessary for cancer control during immunotherapy E Brenner , B Schorg , T Wieder , H Braumuller , M Kneilling , J Bauer , K Ghoreschi , A Yazdi and M Rocken 1 Dermatology, Eberhard Karls University, Tubingen, Germany and 2 Preclinical Imaging and Radiopharmacy, Eberhard Karls University, Tubingen, Germany 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 Tantigen (Tag) under the insulin promoter. Besides partial killing of tumor cells, therapy with immune-checkpoint inhibitors induced type I immunity, a p16/Ki67 senescent 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. 069 Genome-wide association study identifies 14 novel risk alleles associated with basal cell carcinoma HS Chahal, W Wu, K Ransohoff, L Yang, H Hedlin, M Desai, Y Lin, H Dai, AA Qureshi, W Li, P Kraft, D Hinds, J Tang, J Han and K Sarin 1 Dermatology, Stanford School of Medicine, Stanford, CA, 2 Epidemiology, Indiana University, Indianapolis, IN, 3 Medicine (Biostatistics), Stanford University, Stanford, CA, 4 Epidemiology and Biostatistics, Tianjin Medical University Cancer Hospital and Institute, Tianjin, China, 5 Dermatology, Brown University, Providence, RI, 6 Epidemiology, Brown University, Providence, RI, 7 Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 8 Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, 9 Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA and 10 23andMe Inc., Mountain View, CA Basal cell carcinoma (BCC) is the most common cancer worldwide and contributes substantially to morbidity. Since 2008, 6 population-based genome-wide association studies (GWAS) of BCC have been reported, identifying 16 regions of susceptibility. To identify additional susceptibility loci, we conducted a two-stage GWAS of 17,187 BCC cases and 287,054 controls, making this the largest BCC GWAS to date. The stage 1 set consisted of 12,945 cases and 274,252 controls from the 23andMe research participant cohort, and stage 2 consisted of 4,242 cases and 12,802 controls from the Nurses’ Health/Health Professionals’ cohort. Meta-analysis of the combined data uncovered 14 novel susceptibility loci for BCC reaching genome-wide significance (P<5 10), and also confirmed 12 previously reported associations. These 14 novel loci, some of which are expression quantitative trait loci or keratinocyte regulatory elements, implicate a diverse set of genes—involved in telomere maintenance, immune regulation, and tumor suppression—in BCC susceptibility. Further investigation of these loci will deepen our understanding of BCC pathogenesis and improve our ability to prevent these common tumors.