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

Molecular mechanism of phosphopeptide neoantigen immunogenicity

Abstract Altered protein phosphorylation in cancer cells often leads to surface presentation of phosphopeptide neoantigens. However, their role in cancer immunogenicity remains unclear. Here we describe a mechanism by which an HLA-B*0702-specific acute myeloid leukemia phosphoneoantigen, pMLL747–755 (EPR(pS)PSHSM), is recognized by a cognate T cell receptor named TCR27, a candidate for cancer immunotherapy. We show that the replacement of phosphoserine P4 with serine or phosphomimetics does not affect pMHC conformation or peptide-MHC affinity but abrogates TCR27-dependent T cell activation and weakens binding between TCR27 and pMHC. Here we describe the crystal structures for TCR27 and cognate pMHC, map of the interface produced by nuclear magnetic resonance, and a ternary complex generated using information-driven protein docking. Our data show that non-covalent interactions between the epitope phosphate group and TCR27 are crucial for TCR specificity. This study supports development of new treatment options for cancer patients through target expansion and TCR optimization

Challenges of multimodality: Language and the body in social interaction

This article reflects on recent challenges emerging from the study of language and the body in social interaction. There is a general interest in language and the body across disciplines that has invited a reconceptualization of the broader issues relative to action, cognition, culture, knowledge, social relations and identities, spatiality and temporality. The study of social interaction focuses on how multimodal resources - including language and bodily movements - are holistically and situatedly used in building human action. This article discusses some consequences and challenges of putting the body at the center of attention: it repositions language as one among other modalities, and invites us to consider the involvement of entire bodies in social interaction, overcoming a logo-centric vision of communication, as well as a visuo-centric vision of embodiment. These issues are developed through a series of conversation analytic studies, firstly of classic topics in linguistics like deixis, then of more recent topics, such as mobility and sensoriality

Historical Context and Hazardous Waste Facility Siting: Understanding Temporal Patterns in Michigan

This article tests the proposition that, beginning in the 1970s, historic growth of public environmental concern and opposition to waste facilities, as well as changes in the policy environment increasingly encouraged hazardous waste facilities siting to follow the path of least (political) resistance and resulted in environmental inequities. Our longitudinal analysis of sitings in the State of Michigan from 1950 to 1990 reveals a distinct temporal pattern supporting our hypotheses. Whereas significant racial, socioeconomic, and housing disparities at the time of siting were not in evidence for facilities sited prior to 1970, patterns of disparate siting were found for facilities sited after 1970. Thus, we call for environmental justice studies employing longitudinal methods to understand the processes and factors contributing to environmental inequalities with greater consideration to changes in historical context