Purpose: Cancer immunotherapy is a potent treatment modality, but its clinical benefit depends on the tumor's immune profile. Here, we used mJX-594 (JX), a targeted and GM-CSF-armed oncolytic vaccinia virus, as a strategy to remodel the tumor microenvironment (TME) and subsequently increase sensitivity to aPD-1 and/or aCTLA-4 immunotherapy.Experimental Design: The remodeling of the TME was determined using histologic, flow-cytometric, and NanoString immune profiling analyses. JX was intratumorally injected into implanted Renca kidney tumors or MMTV-PyMT transgenic mouse breast cancers with or without aPD-1 and/or aCTLA-4. Various combination regimens were used to evaluate immunotherapeutic anticancer responses.Results: Intratumoral injection of JX remodeled the TME through dynamic changes in the immune system, as shown by increased tumor-infiltrating T cells and upregulation of immune-related gene signatures. This remodeling induced conversion of a noninflamed tumor into an inflamed tumor. JX virotherapy led to enhanced abscopal effects in distant tumors, with increased intratumoral infiltration of CD8 þ T cells. A depletion study revealed that GM-CSF is an indispensable regulator of anticancer efficacy of JX. Dualcombination therapy with intratumoral JX and systemic aPD-1 or aCTLA-4 further enhanced the anticancer immune response, regardless of various treatment schedules. Of note, triple combination immunotherapy with JX, aPD-1, and aCTLA-4 elicited the most potent anticancer immunity and induced complete tumor regression and long-term overall survival.Conclusions: Our results show that intratumoral JX treatment induces dramatic remodeling of the TME and more potently suppresses cancer progression with immunecheckpoint blockades by overcoming resistance to immunotherapy.

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Resilience to aversive events has a central role in determining whether stress leads to the development of depression. mGluR5 has been implicated in the pathophysiology of depression, but the effect of mGluR5 activity on stress resilience remains unexplored. We found that mGluR5(-/-) (also known as Grm5(-/-)) mice displayed more depression-like behaviors (for example, learned helplessness, social withdrawal and anhedonia) than control mice following exposure to various stressful stimuli. Lentiviral 'rescue' of mGluR5 in the nucleus accumbens (NAc) decreased these depression-like behaviors in mGluR5(-/-) mice. In the NAc, ΔFosB, whose induction promotes stress resilience, failed to be upregulated by stress in mGluR5(-/-) mice. Notably, targeted pharmacological activation of mGluR5 in the NAc increased ΔFosB expression. Our findings point to an essential role for mGluR5 in promoting stress resilience and suggest that a defect in mGluR5-mediated signaling in the NAc may represent an endophenotype for stress-induced depression.

Abstract-This article describes an approach to detecting mental stress using unobtrusive wearable sensors. The approach relies on estimating the state of the autonomic nervous system from an analysis of heart rate variability. Namely, we use a non-linear system identification technique known as principal dynamic modes (PDM) to predict the activation level of the two autonomic branches: sympathetic (i.e. stress-inducing) and parasympathetic (i.e. relaxationrelated). We validate the method on a discrimination problem with two psychophysiological conditions, one associated with mental tasks and one induced by relaxation exercises. Our results indicate that PDM features are more stable and less subject-dependent than spectral features, though the latter provide higher classification performance within subjects. When PDM and spectral features are combined, our system discriminates stressful events with a success rate of 83% within subjects (69% between subjects).

Abstract-Chronic stress is endemic to modern society. However, as it is unfeasible for physicians to continuously monitor stress levels, its diagnosis is nontrivial. Wireless body sensor networks offer opportunities to ubiquitously detect and monitor mental stress levels, enabling improved diagnosis, and early treatment. This article describes the development of a wearable sensor platform to monitor a number of physiological correlates of mental stress. We discuss tradeoffs in both system design and sensor selection to balance information content and wearability. Using experimental signals collected from the wearable sensor, we describe a selected number of physiological features that show good correlation with mental stress. In particular, we propose a new spectral feature that estimates the balance of the autonomic nervous system by combining information from the power spectral density of respiration and heart rate variability. We validate the effectiveness of our approach on a binary discrimination problem when subjects are placed under two psychophysiological conditions: mental stress and relaxation. When used in a logistic regression model, our feature set is able to discriminate between these two mental states with a success rate of 81% across subjects.Index Terms-Electrodermal activity, heart rate variability, mental stress, wearable sensors.