CTLA4 blockade abrogates KEAP1/STK11-related resistance to PD-(L)1 inhibitors.

For patients with advanced non-small-cell lung cancer (NSCLC), dual immune checkpoint blockade (ICB) with CTLA4 inhibitors and PD-1 or PD-L1 inhibitors (hereafter, PD-(L)1 inhibitors) is associated with higher rates of anti-tumour activity and immune-related toxicities, when compared with treatment with PD-(L)1 inhibitors alone. However, there are currently no validated biomarkers to identify which patients will benefit from dual ICB1,2. Here we show that patients with NSCLC who have mutations in the STK11 and/or KEAP1 tumour suppressor genes derived clinical benefit from dual ICB with the PD-L1 inhibitor durvalumab and the CTLA4 inhibitor tremelimumab, but not from durvalumab alone, when added to chemotherapy in the randomized phase III POSEIDON trial3. Unbiased genetic screens identified loss of both of these tumour suppressor genes as independent drivers of resistance to PD-(L)1 inhibition, and showed that loss of Keap1 was the strongest genomic predictor of dual ICB efficacy-a finding that was confirmed in several mouse models of Kras-driven NSCLC. In both mouse models and patients, KEAP1 and STK11 alterations were associated with an adverse tumour microenvironment, which was characterized by a preponderance of suppressive myeloid cells and the depletion of CD8+ cytotoxic T cells, but relative sparing of CD4+ effector subsets. Dual ICB potently engaged CD4+ effector cells and reprogrammed the tumour myeloid cell compartment towards inducible nitric oxide synthase (iNOS)-expressing tumoricidal phenotypes that-together with CD4+ and CD8+ T cells-contributed to anti-tumour efficacy. These data support the use of chemo-immunotherapy with dual ICB to mitigate resistance to PD-(L)1 inhibition in patients with NSCLC who have STK11 and/or KEAP1 alterations.

A comparison between auditory hallucinations, interpretation of voices, and formal thought disorder in dissociative identity disorder and schizophrenia spectrum disorders.

OBJECTIVES: Dissociative identity disorder (DID) and schizophrenia-spectrum disorders (SSD) share some overlapping phenomenological features making accurate diagnosis more difficult. Childhood abuse and depersonalization have been associated with psychotic symptoms across psychological disorders but their relationship to psychotic phenomenology remains understudied. METHOD: The present study used quantitative measures to examine (1) similarities and differences in phenomenological voice hearing experiences, interpretations of voices, and thought disorder symptoms in individuals with DID (n = 44) or SSD (n = 45), and (2) whether depersonalization and childhood maltreatment influenced the initial pattern of findings. RESULTS: DID participants perceived their voices as being more internally located and generated, louder, and uncontrollable than SSD participants. Furthermore, the DID participants endorsed a greater frequency of thought disorder symptoms. Adding the covariates (sex, depersonalization, and child maltreatment) did not change the findings associated with location and origin of voices, and derailment, but there were now no differences in loudness or controllability. However, the schizophrenia sample reported more distress and metaphysical beliefs associated with voices, as well as more thought disorder incoherence and word substitution with the covariates controlled. CONCLUSION: While tentative, metaphysical interpretations of voices, incoherent thoughts and word substitution may reflect more psychotic processes.

Dissociation as a Mediator Between Childhood Abuse and Hallucinations: An Exploratory Investigation Using Dissociative Identity Disorder and Schizophrenia Spectrum Disorders.

Previous research has shown that the relationship between childhood abuse and the presence of auditory hallucinations is mediated by dissociation, specifically depersonalization and absorption. The current study assessed dissociation as a mediator of the relationship between childhood abuse and auditory hallucination frequency, characteristics and associated distress in those with dissociative identity disorder (DID; n = 50) and schizophrenia spectrum disorders (SSD; n = 49). It also tested whether dissociation mediated the relationship between childhood abuse and the presence of non-auditory hallucinations. Participants completed measures of childhood abuse, dissociation, auditory hallucination frequency, characteristics, distress, and non-auditory hallucinations. With distress associated with auditory hallucinations as the outcome, depersonalization was a mediator in the DID group. For non-auditory hallucinations, in the DID group depersonalization and amnesia were mediators between childhood abuse and the presence of visual, tactile and olfactory hallucinations. In the SSD group absorption mediated between childhood abuse and visual, olfactory and gustatory hallucinations. Results suggest that the presence of non-auditory hallucinations in DID and SSD are associated with different dissociative experiences.

Lensless photography with only an image sensor.

Photography usually requires optics in conjunction with a recording device (an image sensor). Eliminating the optics could lead to new form factors for cameras. Here, we report a simple demonstration of imaging using a bare CMOS sensor that utilizes computation. The technique relies on the space variant point-spread functions resulting from the interaction of a point source in the field of view with the image sensor. These space-variant point-spread functions are combined with a reconstruction algorithm in order to image simple objects displayed on a discrete LED array as well as on an LCD screen. We extended the approach to video imaging. Finally, we performed experiments to analyze the parametric impact of the object distance. Improving the sensor designs and reconstruction algorithms can lead to useful cameras without optics.

TREM1 activation of myeloid cells promotes antitumor immunity.

Myeloid cells in the tumor microenvironment (TME) can exist in immunosuppressive and immunostimulatory states that impede or promote antitumor immunity, respectively. Blocking suppressive myeloid cells or increasing stimulatory cells to enhance antitumor immune responses is an area of interest for therapeutic intervention. Triggering receptor expressed on myeloid cells-1 (TREM1) is a proinflammatory receptor that amplifies immune responses. TREM1 is expressed on neutrophils, subsets of monocytes and tissue macrophages, and suppressive myeloid populations in the TME, including tumor-associated neutrophils, monocytes, and tumor-associated macrophages. Depletion or inhibition of immunosuppressive myeloid cells, or stimulation by TREM1-mediated inflammatory signaling, could be used to promote an immunostimulatory TME. We developed PY159, an afucosylated humanized anti-TREM1 monoclonal antibody with enhanced FcγR binding. PY159 is a TREM1 agonist that induces signaling, leading to up-regulation of costimulatory molecules on monocytes and macrophages, production of proinflammatory cytokines and chemokines, and enhancement of T cell activation in vitro. An antibody against mouse TREM1, PY159m, promoted antitumor efficacy in syngeneic mouse tumor models. These results suggest that PY159-mediated agonism of TREM1 on tumoral myeloid cells can promote a proinflammatory TME and offer a promising strategy for immunotherapy.

Targeting TREM2 on tumor-associated macrophages enhances immunotherapy.

Converting checkpoint inhibitor (CPI)-resistant individuals to being responsive requires identifying suppressive mechanisms. We identify TREM2+ tumor-associated macrophages (TAMs) as being correlated with exhausted CD8+ tumor-infiltrating lymphocytes (TILs) in mouse syngeneic tumor models and human solid tumors of multiple histological types. Fc domain-enhanced anti-TREM2 monoclonal antibody (mAb) therapy promotes anti-tumor immunity by elimination and modulation of TAM populations, which leads to enhanced CD8+ TIL infiltration and effector function. TREM2+ TAMs are most enriched in individuals with ovarian cancer, where TREM2 expression corresponds to disease grade accompanied by worse recurrence-free survival. In an aggressive orthotopic ovarian cancer model, anti-TREM2 mAb therapy drives potent anti-tumor immunity. These results highlight TREM2 as a highly attractive target for immunotherapy modulation in individuals who are refractory to CPI therapy and likely have a TAM-rich tumor microenvironment.

Delusional beliefs and their characteristics: A comparative study between dissociative identity disorder and schizophrenia spectrum disorders.

Firmly held beliefs that have a delusional quality are commonly experienced in those with schizophrenia spectrum disorders (SSD) and have been reported in those with dissociative identity disorder (DID). However, no study to date has compared delusional belief content and characteristics between these diagnostic groups. This study examined delusional content, and the degree of conviction, preoccupation and distress associated with them in 50 participants with DID and 50 with an SSD exploring also dissociation and childhood trauma as predictors of delusional beliefs. Multivariate analysis of variance and linear regressions were conducted to explore differences between beliefs and characteristics and to examine their association with dissociation and childhood trauma. The SSD sample presented more self-referential delusional beliefs and characteristics compared to the DID group. Yet, the DID group had more mistrust delusional beliefs and characteristics in comparison to SSD participants. Mistrust beliefs were predicted by depersonalization/derealization in the DID sample, but did not predict any delusional belief in the SSD sample. The content of fixed beliefs differs between DID and SSD samples and in this study depersonalization/derealization experiences were related to mistrust beliefs but not to other delusional forms, and only in the DID sample.