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<p>Pre-clinical and clinical data strongly support the use of immunotherapies for cancer treatment. Cancer vaccines offer a promising approach, however, the outcomes of clinical vaccine trials have been largely disappointing, prompting a need for further investigation. Using the B16F10 murine melanoma, we have investigated the local events within growing tumors following recombinant adenovirus immunization. In chapter 2, we investigated the ability of a pre-clinical vaccine to elicit only transient tumor growth suppression. We observed that tumors were initially infiltrated by a small number of highly functional tumor-specific CD8+ T cells following vaccination that instigated a rapid adaptive response in the tumor that suppressed local immune activity. In chapter 3, we questioned whether increasing the rate and magnitude of early immune attack would result in more robust tumor attack prior to tumor adaptation. Increasing the rate of tumor-specific CD8+ T cell expansion following vaccination resulted in tumor regression and durable cures in approximately 65% of treated mice. Further analysis revealed that tumor regression correlated with an early burst in immune attack that outpaced tumor adaptation. In chapter 4, we explored whether the same vaccine could be improved when combined with immunomodulatory antibodies. Vaccination combined with anti 4-1BB and anti PD-1 resulted in complete tumor regression and durable cure of >70% of treated animals and was associated with increased local immune activity. Gene expression profiling revealed a unique gene signature associated with the curative treatment, which was also associated with positive outcome in human melanoma patients. The described research sheds new light on mechanisms that limit the efficacy of therapeutic cancer vaccines. Namely, rapid tumor adaptation, triggered by early vaccine-induced CD8+ T cells, acts to suppress the local immune response prior to maximal immune attack. Strategies to overcome these adaptive processes should therefore be considered in future vaccine design.</p> / Doctor of Philosophy (Medical Science)

Social anxiety and depression are commonly comorbid, and together they result in greater functional impairment and a poorer prognosis than when either condition occurs alone. Although the onset of social anxiety precedes the development of depression in the large majority of comorbid cases, little research has directly examined factors that contribute to the occurrence of depression in individuals with social anxiety. Theoretical models implicate emotion and emotion regulation in the development and maintenance of internalizing disorders. Emotion regulation research has predominantly focused on expressive suppression (ES), the suppression of outward emotion, and cognitive reappraisal (CR), the modification of cognitions to manage emotion. Social anxiety and depression are both characterized by maladaptive patterns of emotion regulation, exhibiting an overreliance on ES and an underutilization of CR. The present study investigated the role of emotion regulation, specifically ES and CR, in the relationship between social anxiety and depression over time. Our primary aim was to evaluate ES and CR, separately, as mediators of the relationship between social anxiety and depression. Our secondary aim was to evaluate additional mediating and/or moderating effects of related variables (i.e., relationship quality, positive and negative affect, and reward sensitivity). Our final exploratory aim was to evaluate whether emotion regulation (i.e., ES and CR) for positive emotions differs from emotion regulation for negative emotions in the relationships proposed by our primary and secondary aims. Undergraduate participants (N=137) completed an in-person laboratory session (i.e., baseline), followed by a 14-day daily diary period. During the daily diary period, participants reported on their daily experiences of social anxiety, depressed mood, emotion, emotion regulation, and relationship quality. Approximately two weeks after the end of the daily diary period (i.e., four weeks after baseline), participants completed a final in-person laboratory session (i.e., endpoint). Multilevel modeling was used to analyze observation-level data over the two-week diary period, and bootstrapping methods were used for person-level analyses over the full four-week study period. Daily diary analyses failed to support the hypothesized mediation models. Average social anxiety across the daily diary period was positively associated with daily depressed mood, but observation-level social anxiety was not. Exploratory analyses revealed affect-specific effects of emotion regulation, such that higher perceived success in ES (i.e., daily ES self-efficacy) for positive affect and less frequent use of CR (i.e., daily CR frequency) for negative affect significantly predicted higher next-day depressed mood. Person-level analyses across the four-week study period yielded some support for our hypotheses, in that ES frequency and positive affect acted as sequential mediators of the relationship between social anxiety and depression. Higher social anxiety predicted more frequent ES, which predicted lower positive affect, which then predicted higher depression. However, the mediation model was no longer significant after controlling for baseline depression. Our results highlight the role of emotion dysregulation in predicting depression and provide initial support for the mediating effects of ES and CR in the relationship between social anxiety and depression. These findings also emphasize the importance of investigating affect-specific effects, with particular attention paid to emotion regulation for positive affect and its role in the co-occurrence of social anxiety and depression. Future research would benefit from longitudinal studies across longer time periods and examining these relationships within a clinical sample. / Psychology

Self-control exertion leads to performance decrements during tasks demanding of muscular and cardiovascular systems (Bray et al., 2008; Marcora et al., 2009). Several reviews have also implicated self-control depletion with the psychobiological state of fatigue (Hagger et al., 2010; Van Cutsem et al., 2017). In this state, individuals have also been noted to report higher levels of perceived exertion when exercising at vigorous intensities (MacMahon et al., 2014; Marcora et al., 2009; Wagstaff et al., 2014). The purpose of this study was to investigate physical performance and ratings of perceived exertion during a self-paced maximum distance cycling trial (MDT) following a short bout of mentally-fatiguing cognitive activity (thought-suppression). Recreationally active participants (N = 16, Mage = 20.94) completed one familiarization session and two testing sessions. All visits were separated by ≥ 72-hours. Control and experimental trials were counterbalanced, with either a 6-minute bout of thought-logging (control) or a 6-minute bout of thought-suppression (experimental) being performed prior to each respective MDT. Ratings of perceived exertion (RPE) were solicited from participants across three sensory domains relevant to MDT task performance (Leg-muscle, Respiration, Mental). Thought-suppression was perceived to be significantly more demanding than the control task, which resulted in significantly higher ratings of mental fatigue (p = 0.04, 2 = 0.26). Distance travelled on the MDT was not significantly different following thought suppression, relative to control trials (p = 0.84, 2 = 0.00). Similarly, a repeated-measures ANOVA showed no differences in HR between conditions (p = 0.95, 2 = 0.00). Despite these similarities, ratings of perceived leg-muscle exertion (RPE-L) were significantly higher during the MDT following thought-suppression (p = 0.05, 2 = 0.24). RPE-R (respiration) and RPE-M (mental) ratings also trended towards higher scores following the experimental manipulation, although they did not differ significantly. RPE-L was perceived to be significantly higher than both RPE-R and RPE-M in both conditions on the MDT (ps < 0.05). RPE-M was rated significantly lower than RPE-L and RPE-R during MDTs in both conditions (ps < 0.05). Results indicate that performing a demanding self-control exertion task for a short duration leads to increased feelings of mental fatigue. The observed levels of fatigue were also associated with higher than normal ratings of perceived exertion during cycling tasks of equal demands and performance. / Thesis / Master of Science (MSc) / Any thought, emotion or behaviour that an individual modifies in order to better suit their goals occurs as a result of self-control exertion. Research indicates that just like the exertion of muscular strength, exerting self-control impacts subsequent attempts to do so. Using a mentally-demanding task, we induced states of self-control depletion which left individuals feeling mentally-fatigued. As a result of this state, participants needed to exert themselves harder in order to complete a task that was perceived less demanding, when non-fatigued.