31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Correlation of nailfold capillaroscopy findings with history of digital ulcer on same finger: Results of SCLEROCAP study

International audienceSystemic sclerosis may be complicated by digital ulcers. Nailfold capillaroscopy on one finger might reflect an increased risk of digital ulcer (DU). In the present study we studied the correlations between a history of ulcer and capillary findings on the finger.Method: This study is part of Sclerocap, a multicenter study aiming at validating prospectively the prognostic value of Maricq's and Cutolo's capillaroscopic classifications during a three-year longitudinal follow-up. A history of past or present digital ulcer was recorded at inclusion and nailfold capillaroscopy was performed. Elementary findings as well as Cutolo and Maricq's classifications were assessed.Results: 387 patients were included in Sclerocap (327 females, 60 males) and 3096 fingers were examined by capillaroscopy at inclusion: 316 fingers (10%) belonging to 113 patients had a history of DU. Late Cutolo's stage was statistically correlated with a history of DU, both by univariate: OR 2.08 [1.09-3.96] and multivariate analysis: OR 1.97 [1.06-3.63]. Among the elemental abnormalities, only edema and decreased capillary density were correlated with a history of DU by multivariate analysis: respectively OR 1.92 [1.17-3.16] and 0.65 [0.49-0.85].Conclusion: This cross-sectional study in a large cohort of patients with systemic sclerosis shows a correlation between a history of digital ulcer and edema, a decrease in capillary density and the late stage in Cutolo's classification. The extent of capillary abnormalities on one finger is associated with a history of local digital ulcer. Capillaroscopy might be used to predict the risk of DU but these results need first to be confirmed by prospective studies

Identification of genetic elements in metabolism by high-throughput mouse phenotyping

Metabolic diseases are a worldwide problem but the underlying genetic factors and their relevance to metabolic disease remain incompletely understood. Genome-wide research is needed to characterize so-far unannotated mammalian metabolic genes. Here, we generate and analyze metabolic phenotypic data of 2016 knockout mouse strains under the aegis of the International Mouse Phenotyping Consortium (IMPC) and find 974 gene knockouts with strong metabolic phenotypes. 429 of those had no previous link to metabolism and 51 genes remain functionally completely unannotated. We compared human orthologues of these uncharacterized genes in five GWAS consortia and indeed 23 candidate genes are associated with metabolic disease. We further identify common regulatory elements in promoters of candidate genes. As each regulatory element is composed of several transcription factor binding sites, our data reveal an extensive metabolic phenotype-associated network of co-regulated genes. Our systematic mouse phenotype analysis thus paves the way for full functional annotation of the genome