Dual control of lysogeny by bacteriophage P22: An antirepressor locus and its controlling elements

Two distantly linked clusters of genes on the Salmonella typhimurium phage P22 chromosome are involved in the control of lysogeny and superinfection immunity. One cluster consists of genes c1, c2, and c3, which are primarily responsible for the establishment and maintenance of lysogeny. It has been proposed that the second cluster consists of three loci which are responsible for the synthesis and control of an antirepressor substance which overcomes the repression mediated by the c2 gene product. This paper reports the isolation of mutants in a locus designated "ant" having characteristics expected of antirepressor mutants. Evidence is presented that the other loci in this second immunity region, mnt and virA, control the expression of the ant gene as represser and promoter/operator, respectively. The interactions of these three loci with each other and with the other immunity region are discussed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/22123/1/0000550.pd

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

Public COAPI Toolkit of Open Access Policy Resources

The Coalition of Open Access Policy Institutions (COAPI, https://sparcopen.org/coapi ) is committed to sharing information and resources to assist in the development and implementation of institutional Open Access (OA) policies. The COAPI Toolkit includes a diverse collection of resources that COAPI members have developed in the course of their OA policy initiatives. These resources are openly accessible and published here under Creative Commons Attribution 4.0 licenses, unless otherwise noted on the resources themselves