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

Auditory and visual distractors disrupt multisensory temporal acuity in the crossmodal temporal order judgment task

The ability to synthesize information across multiple senses is known as multisensory integration and is essential to our understanding of the world around us. Sensory stimuli that occur close in time are likely to be integrated, and the accuracy of this integration is dependent on our ability to precisely discriminate the relative timing of unisensory stimuli (crossmodal temporal acuity). Previous research has shown that multisensory integration is modulated by both bottom-up stimulus features, such as the temporal structure of unisensory stimuli, and top-down processes such as attention. However, it is currently uncertain how attention alters crossmodal temporal acuity. The present study investigated whether increasing attentional load would decrease crossmodal temporal acuity by utilizing a dual-task paradigm. In this study, participants were asked to judge the temporal order of a flash and beep presented at various temporal offsets (crossmodal temporal order judgment (CTOJ) task) while also directing their attention to a secondary distractor task in which they detected a target stimulus within a stream visual or auditory distractors. We found decreased performance on the CTOJ task as well as increases in both the positive and negative just noticeable difference with increasing load for both the auditory and visual distractor tasks. This strongly suggests that attention promotes greater crossmodal temporal acuity and that reducing the attentional capacity to process multisensory stimuli results in detriments to multisensory temporal processing. Our study is the first to demonstrate changes in multisensory temporal processing with decreased attentional capacity using a dual task paradigm and has strong implications for developmental disorders such as autism spectrum disorders and developmental dyslexia which are associated with alterations in both multisensory temporal processing and attention

Visual Distractors Disrupt Audiovisual Integration Regardless of Stimulus Complexity

The intricate relationship between multisensory integration and attention has been extensively researched in the multisensory field; however, the necessity of attention for the binding of multisensory stimuli remains contested. In the current study, we investigated whether diverting attention from well-known multisensory tasks would disrupt integration and whether the complexity of the stimulus and task modulated this interaction. A secondary objective of this study was to investigate individual differences in the interaction of attention and multisensory integration. Participants completed a simple audiovisual speeded detection task and McGurk task under various perceptual load conditions: no load (multisensory task while visual distractors present), low load (multisensory task while detecting the presence of a yellow letter in the visual distractors), and high load (multisensory task while detecting the presence of a number in the visual distractors). Consistent with prior studies, we found that increased perceptual load led to decreased reports of the McGurk illusion, thus confirming the necessity of attention for the integration of speech stimuli. Although increased perceptual load led to longer response times for all stimuli in the speeded detection task, participants responded faster on multisensory trials than unisensory trials. However, the increase in multisensory response times violated the race model for no and low perceptual load conditions only. Additionally, a geometric measure of Miller’s inequality showed a decrease in multisensory integration for the speeded detection task with increasing perceptual load. Surprisingly, we found diverging changes in multisensory integration with increasing load for participants who did not show integration for the no load condition: no changes in integration for the McGurk task with increasing load but increases in integration for the detection task. The results of this study indicate that attention plays a crucial role in multisensory integration for both highly complex and simple multisensory tasks and that attention may interact differently with multisensory processing in individuals who do not strongly integrate multisensory information

Features of the psychometric function.

<p>Individual participant data was fit with a psychometric function for each perceptual load. The resulting mean PSS (A), nJND (B), and pJND (C) are shown grouped by the modality of the distractor task. Both the nJND and pJND, but not the PSS, increased with increasing load. No significant effects of distractor modality were found. Error bars represent SEM. * Indicate significant differences (p < .0125) as compared to NL.</p

Percent flash first reports across SOA for the CTOJ task separated by visual versus auditory distractor tasks.

<p>SOA significantly influenced the percent of flash-first reports with positive SOAs (visual leading) resulting in more visual first reports. SOA and perceptual load significantly interacted for both distractor modalities indicating that perceptual load modulates performance on the CTOJ task. Error bars represent the SEM. * indicate significant differences between NL and HL and/or NL and LL at the Bonferroni-corrected alpha level of p < .0018.</p

Performance on the visual and auditory distractor tasks.

<p>Accuracy was lower for HL compared to LL for both visual and auditory distractors. Additionally, accuracy was higher for the visual distractor task then the auditory distractor task. Error bars represent SEM. * Indicate significance differences between LL and HL.</p