Macrophages impede CD8 T cells from reaching tumor cells and limit the efficacy of anti-PD-1 treatment.

In a large proportion of cancer patients, CD8 T cells are excluded from the vicinity of cancer cells. The inability of CD8 T cells to reach tumor cells is considered an important mechanism of resistance to cancer immunotherapy. We show that, in human lung squamous-cell carcinomas, exclusion of CD8 T cells from tumor islets is correlated with a poor clinical outcome and with a low lymphocyte motility, as assessed by dynamic imaging on fresh tumor slices. In the tumor stroma, macrophages mediate lymphocyte trapping by forming long-lasting interactions with CD8 T cells. Using a mouse tumor model with well-defined stromal and tumor cell areas, macrophages were depleted with PLX3397, an inhibitor of colony-stimulating factor-1 receptor (CSF-1R). Our results reveal that a CSF-1R blockade enhances CD8 T cell migration and infiltration into tumor islets. Although this treatment alone has minor effects on tumor growth, its combination with anti-PD-1 therapy further increases the accumulation of CD8 T cells in close contact with malignant cells and delays tumor progression. These data suggest that the reduction of macrophage-mediated T cell exclusion increases tumor surveillance by CD8 T cells and renders tumors more responsive to anti-PD-1 treatment.

Profiles of Emotion Dysregulation Among University Students Who Self-Injure: Associations with Parent-Child Relationships and Non-Suicidal Self-Injury Characteristics.

More research is needed to understand the different vulnerability profiles of university students who engage in non-suicidal self-injury (NSSI). This study sought to classify university students (n = 479; 83.8% female) aged 17-25 years (M = 18.77; SD = 1.42) who had engaged in NSSI within the past year into latent profiles based on their self-perceived difficulties in regulating both positive and negative emotions. Independent samples of students who had a past history of NSSI but had not self-injured within the previous year (n = 439; 82.9% females; Mage = 19.03, SD = 1.62) and who had no history of NSSI (n = 1551; 69.9% females; Mage = 19.02, SD = 1.55) were recruited for comparison purposes. Latent cluster analyses revealed three emotion regulation profiles within the NSSI sample-the Average Difficulties (47.4%), Dysregulated (33.0%), and Low Difficulties (19.6%) profiles-each of which differed meaningfully from both comparison samples on mean emotion regulation difficulties. Students across profiles also differed in their self-reported experiences with parents, particularly with fathers (pressure, antipathy, unresolved attachment, psychological control), and in the extent to which they felt alienated from parents. Lastly, students across profiles differed in the frequency, methods, functions, and addictive properties of their NSSI. Findings highlight that university students who self-injure experience distinct patterns of difficulties with emotion regulation, which are associated with variation in parent-child relational risk factors and NSSI outcomes.

Invalidating Caregiving Environments, Specific Emotion Regulation Deficits, and Non-suicidal Self-injury.

This study examined the indirect effects of distinct aspects of invalidating caregiving environments (i.e., paternal maltreatment, maternal maltreatment, and perceived alienation) on non-suicidal self-injury (NSSI) via six specific emotion regulation difficulties. We hypothesized that specific emotion regulation deficits would mediate associations between invalidating environments and NSSI. Participants included 114 young adults (57 self-injurers; 57 age- and sex-matched comparison participants) aged 17-25 years. Three parallel mediation models tested hypotheses. Results showed that maternal maltreatment, paternal maltreatment, and perceived alienation indirectly predicted NSSI through poor emotional clarity. Maternal maltreatment uniquely predicted NSSI through limited access to regulation strategies. Lastly, maternal maltreatment and perceived alienation were both linked to greater difficulties engaging in goal-directed behavior during emotional upsets; however, contrary to hypotheses, this particular deficit was associated with decreased odds of engaging in NSSI. Findings illustrate how different aspects of invalidating environments and specific emotion regulation deficits may be implicated in NSSI engagement.

Anti-PD-1 therapy triggers Tfh cell-dependent IL-4 release to boost CD8 T cell responses in tumor-draining lymph nodes.

Anti-PD-1 therapy targets intratumoral CD8+ T cells to promote clinical responses in cancer patients. Recent evidence suggests an additional activity in the periphery, but the underlying mechanism is unclear. Here, we show that anti-PD-1 mAb enhances CD8+ T cell responses in tumor-draining lymph nodes by stimulating cytokine production in follicular helper T cells (Tfh). In two different models, anti-PD-1 mAb increased the activation and proliferation of tumor-specific T cells in lymph nodes. Surprisingly, anti-PD-1 mAb did not primarily target CD8+ T cells but instead stimulated IL-4 production by Tfh cells, the major population bound by anti-PD-1 mAb. Blocking IL-4 or inhibiting the Tfh master transcription factor BCL6 abrogated anti-PD-1 mAb activity in lymph nodes while injection of IL-4 complexes was sufficient to recapitulate anti-PD-1 mAb activity. A similar mechanism was observed in a vaccine model. Finally, nivolumab also boosted human Tfh cells in humanized mice. We propose that Tfh cells and IL-4 play a key role in the peripheral activity of anti-PD-1 mAb.

Tumor-intrinsic sensitivity to the pro-apoptotic effects of IFN-γ is a major determinant of CD4+ CAR T-cell antitumor activity.

CD4+ T cells and CD4+ chimeric antigen receptor (CAR) T cells display highly variable antitumor activity in preclinical models and in patients; however, the mechanisms dictating how and when CD4+ T cells promote tumor regression are incompletely understood. With the help of functional intravital imaging, we report that interferon (IFN)-γ production but not perforin-mediated cytotoxicity was the dominant mechanism for tumor elimination by anti-CD19 CD4+ CAR T cells. Mechanistically, mouse or human CD4+ CAR T-cell-derived IFN-γ diffused extensively to act on tumor cells at distance selectively killing tumors sensitive to cytokine-induced apoptosis, including antigen-negative variants. In anti-CD19 CAR T-cell-treated patients exhibiting elevated CAR CD4:CD8 ratios, strong induction of serum IFN-γ was associated with increased survival. We propose that the sensitivity of tumor cells to the pro-apoptotic activity of IFN-γ is a major determinant of CD4+ CAR T-cell efficacy and may be considered to guide the use of CD4+ T cells during immunotherapy.

Dynamic CD8+ T Cell Cooperation with Macrophages and Monocytes for Successful Cancer Immunotherapy.

The essential roles endorsed by macrophages and monocytes are well established in response to infections, where they contribute to launching the differentiation of specific T-lymphocytes for long-term protection. This knowledge is the result of dynamic studies that can inspire the cancer field, particularly now that cancer immunotherapies elicit some tumor regression. Indeed, immune responses to cancer have mainly been studied after tumors have escaped immune attacks. In particular, the suppressive functions of macrophages were revealed in this context, introducing an obvious bias across the literature. In this review, we will focus on the ways inwhich monocytes and macrophages cooperate with T-lymphocytes, leading to successful immune responses. We will bring together the preclinical studies that have revealed the existence of such positive cooperation in the cancer field, and we will place particular emphasis on proposing the underlying mechanisms. Finally, we will give some perspectives to decipher the functional roles of such T-cell and myeloid cell interactions in the frame of human cancer immunotherapy.

Preclinical murine tumor models: a structural and functional perspective.

The goal of this review is to pinpoint the specific features, including the weaknesses, of various tumor models, and to discuss the reasons why treatments that are efficient in murine tumor models often do not work in clinics. In a detailed comparison of transplanted and spontaneous tumor models, we focus on structure-function relationships in the tumor microenvironment. For instance, the architecture of the vascular tree, which depends on whether tumor cells have gone through epithelial-mesenchymal transition, is determinant for the extension of the spontaneous necrosis, and for the intratumoral localization of the immune infiltrate. Another key point is the model-dependent abundance of TGFß in the tumor, which controls the variable susceptibility of different tumor models to treatments. Grounded in a historical perspective, this review provides a rationale for checking factors that will be key for the transition between preclinical murine models and clinical applications.

Developmental and attachment-based perspectives on dissociation: beyond the effects of maltreatment.

Background: Numerous years of theory and research have informed our understanding of the caregiving experiences that confer vulnerability for dissociation. This work has resulted in widespread agreement on the role of childhood maltreatment as an aetiological factor. Objective: With clear integration of this perspective, the current paper draws attention to the spectrum of vulnerability that can exist over and above the trauma of maltreatment within early caregiving experiences. Method: An integrative review of the developmental literature on dissociation is presented. Results: We first review and integrate existing developmental theories of dissociation into a more unified perspective, highlighting a combination of defensive and intersubjective pathways towards dissociative outcomes. Next, we present empirical research demonstrating which specific caregiving experiences are associated with dissociation. Lastly, we review recent neurodevelopmental research demonstrating that (non-extreme) caregiving stressors during infancy impact the developing limbic structures in the brain. We conclude by offering directions for future research. Conclusion: Findings make the case for approaching assessments of the caregiver-child relationship with discernment of factors beyond the presence/absence of maltreatment when conceptualizing risk pathways toward dissociation.

Antecedentes: Varios años de teoría, investigación y avances clínicos sustentan nuestra comprensión de experiencias particulares en el cuidado temprano que confieren vulnerabilidad para la disociación. Este trabajo ha dado lugar a un acuerdo generalizado sobre el papel del maltrato infantil como un factor etiológico.Objetivo: Con una clara integración de esta perspectiva, el presente artículo enfatiza el espectro de vulnerabilidad que puede existir más allá del trauma que constituye el maltrato dentro de las experiencias de cuidado tempranas.Método: Se presenta una revisión integradora de la literatura del desarrollo sobre la disociación.Resultados: Primero, revisamos e integramos las teorías del desarrollo existentes sobre la disociación en una perspectiva más unificada, resaltando una combinación de vías defensivas e intersubjetivas que resultan en disociación. Luego, presentamos una investigación empírica que demuestra qué experiencias específicas en el cuidado temprano están asociadas con la disociación. Finalmente, revisamos una investigación reciente en neurodesarrollo que demuestra que los estresores (no extremos) durante el cuidado en lainfancia impactan el desarrollo de las estructuras límbicas del cerebro.Conclusión: Los hallazgos justifican abordar las evaluaciones de la relación cuidador-niño con el discernimiento de factores más allá de la presencia/ausencia de maltrato al conceptualizar las vías de riesgo de disociación.

Local IFNα enhances the anti-tumoral efficacy of systemic anti-PD1 to prevent tumor relapse.

BACKGROUND: Tumor relapse constitutes a major challenge for anti-tumoral treatments, including immunotherapies. Indeed, most cancer-related deaths occur during the tumor relapse phase. METHODS: We designed a mouse model of tumor relapse in which mice transplanted with E7+ TC1 tumor cells received a single therapeutic vaccination of STxB-E7+IFNα. Unlike the complete regression observed after two vaccinations, such a treatment induced a transient shrinkage of the tumor mass, followed by a rapid tumor outgrowth. To prevent this relapse, we tested the efficacy of a local administration of IFNα together with a systemic therapy with anti-PD1 Ab. The immune response was analyzed during both the tumor regression and relapse phases. RESULTS: We show that, during the regression phase, tumors of mice treated with a single vaccination of STxB-E7 + IFNα harbor fewer activated CD8 T cells and monocytes than tumors doomed to fully regress after two vaccinations. In contrast, the systemic injection of an anti-PD1 Ab combined with the peri-tumoral injection of IFNα in this time frame promotes infiltration of activated CD8 T cells and myeloid cells, which, together, exert a high cytotoxicity in vitro against TC1 cells. Moreover, the IFNα and anti-PD1 Ab combination was found to be more efficient than IFNα or anti-PD1 used alone in preventing tumor relapse and was better able to prolong mice survival. CONCLUSIONS: Together, these results indicate that the local increase of IFNα in combination with an anti-PD1 therapy is an effective way to promote efficient and durable innate and adaptive immune responses preventing tumor relapse.

The Remarkable Plasticity of Macrophages: A Chance to Fight Cancer.

It is well established that tumor-associated macrophages (TAM) found in most advanced tumors have a pro-tumoral role. In this context, TAM limit the activity of tumor-infiltrating lymphocytes (TIL), and a number of mechanisms have been described including a trapping in the stroma, impeding TIL to reach malignant cells. Based on these results, a number of therapeutic approaches have been designed to deplete TAM. However, during tumor regression induced by immunotherapeutic treatments, recent studies revealed that TAM can switch from pro-tumoral to anti-tumoral and actively cooperate with TIL. Here, we will review the two faces of TAM in their interaction with TIL. We will summarize how they can inhibit T cell activities in growing tumors, and how they may also, together with T cells, successfully contribute to tumor eradication after an appropriate stimulation. Finally, we will discuss current promising therapies combining TAM reprogramming with T cell-based immunotherapy.

TGFß blocks IFNα/ß release and tumor rejection in spontaneous mammary tumors.

Type I interferons (IFN) are being rediscovered as potent anti-tumoral agents. Activation of the STimulator of INterferon Genes (STING) by DMXAA (5,6-dimethylxanthenone-4-acetic acid) can induce strong production of IFNα/ß and rejection of transplanted primary tumors. In the present study, we address whether targeting STING with DMXAA also leads to the regression of spontaneous MMTV-PyMT mammary tumors. We show that these tumors are refractory to DMXAA-induced regression. This is due to a blockade in the phosphorylation of IRF3 and the ensuing IFNα/ß production. Mechanistically, we identify TGFß, which is abundant in spontaneous tumors, as a key molecule limiting this IFN-induced tumor regression by DMXAA. Finally, blocking TGFß restores the production of IFNα by activated MHCII+ tumor-associated macrophages, and enables tumor regression induced by STING activation. On the basis of these findings, we propose that type I IFN-dependent cancer therapies could be greatly improved by combinations including the blockade of TGFß.

Associations between mother-preschooler attachment and maternal depression symptoms: A systematic review and meta-analysis.

The current study aimed to systematically review and meta-analyze concurrent and longitudinal associations between maternal depression symptoms and mother-child attachment during the preschool period (aged 2 to 7 years) as assessed using the coding systems by Cassidy and Marvin (1992) and Main and Cassidy (1988). The review was pre-registered with PROSPERO (International Prospective Register of Systematic Reviews; Registration number CRD42017073417) and was conducted in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. A total of 7,969 records were screened and 18 articles were deemed as eligible for inclusion in the review. Studies were reviewed using qualitative synthesis techniques and, where appropriate, meta-analysis. Qualitative synthesis indicated that mothers of disorganized/controlling children most consistently reported the highest levels of depressive symptoms, both concurrently and longitudinally. The association between disorganized/controlling child attachment and concurrent maternal depressive symptoms was significant (n = 1,787; g = 0.27, 95% CI [0.13,0.40]), and was not moderated by sample type, child gender, or risk of bias. Findings of a relationship between child attachment insecurity and maternal depressive symptoms must be qualified due to significant within-study heterogeneity and publication bias. Results suggest that maternal depressive symptoms may confer risk for disorganized/controlling attachment during the preschool period.

The functions and addictive features of non-suicidal self-injury: A confirmatory factor analysis of the Ottawa self-injury inventory in a university sample.

The Ottawa Self-Injury Inventory (OSI) is a comprehensive self-report measure of non-suicidal self-injury (NSSI). In an effort to build on past research and further validate the OSI, this study presents a confirmatory factor analysis of the OSI's subscales measuring the functions and addictive features of NSSI using a university sample. Participants were 316 university students aged 17-25 years (84.8% female) who had engaged in NSSI at least once in their lifetime. Consistent with past research, results confirmed the four-factor structure of the Functions items (Internal Emotion Regulation, Social Influence, External Emotion Regulation, Sensation Seeking), as well as the single-factor structure of Addictive Features items. Correlations calculated between the obtained factors and indicators of NSSI severity revealed that higher endorsement of NSSI's Internal Emotion Regulation functions, External Emotion Regulation functions, and Addictive Features were associated with more frequent lifetime NSSI, recent (past 6 months) NSSI, and greater distress regarding NSSI urges; greater endorsement of NSSI's Sensation Seeking functions was also linked with more frequent lifetime NSSI. Results provide further support for the OSI's psychometric properties in a university sample, and offer additional evidence for links between specific NSSI functions and addictive features and more severe manifestations of the behavior.

Specific coping strategies moderate the link between emotion expression deficits and nonsuicidal self-injury in an inpatient sample of adolescents.

BACKGROUND: Non-suicidal self-injury (NSSI) is a behavior of increasing prevalence in adolescents with links to various negative mental health and adjustment outcomes. Poor emotion expression has been linked with NSSI use, whereas the use of adaptive coping strategies has been identified as a protective factor against NSSI. The current study examined whether specific coping strategies moderate the relation between poor emotion expression and NSSI, and whether moderation is conditional on adolescent gender. METHODS: Ninety-five adolescents hospitalized on an acute care inpatient psychiatric unit completed questionnaires measuring NSSI, emotion expression and use of specific coping strategies (i.e., problem-focused coping, positive reframing coping, support seeking, avoidance, and distraction). RESULTS: Results indicated that poor emotion expression was positively associated with NSSI. Positive reframing and support seeking emerged as significant moderators of the poor emotion expression-NSSI link. This result was not conditional upon adolescent gender. Problem-focused coping, avoidance, and distraction did not emerge as significant moderators. CONCLUSIONS: Encouraging youth to use particular coping strategies might protect against the negative impact of emotion expression deficits for both boys and girls.

The STING agonist DMXAA triggers a cooperation between T lymphocytes and myeloid cells that leads to tumor regression.

Regressing tumors are usually associated with a large immune infiltrate, but the molecular and cellular interactions that govern a successful anti-tumor immunity remain elusive. Here, we have triggered type I Interferon (IFN) signaling in a breast tumor model (MMTV-PyMT) using 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a ligand of the STimulator of Interferon Genes, STING. The 2 main events rapidly triggered by DMXAA in transplanted PyMT tumors are 1) the disruption of the tumor vasculature, followed by hypoxia and cell death; 2) the release of chemokines. Both events converged to trigger the recruitment of 2 waves of immune cells: a swift, massive recruitment of neutrophils, followed by a delayed rise in monocytes and CD8 T cells in the tumor mass. Depletion experiments in vivo revealed that myeloid cell subsets and T cells need to cooperate to achieve full-blown recruitment and activation at the tumor site and to induce effective secondary cell death leading to tumor regression (Illustration 1). Altogether, our study highlights that the tumor regression induced by the STING agonist DMXAA results from a cascade of events, with an initial vessel destruction followed by several infiltration waves of immune cells which have to cooperate to amplify and sustain the initial effect. We thus provide the first global and detailed kinetic analysis of the anti-tumoral effect of DMXAA and of its different articulated steps.