Selective SIRPα blockade reverses tumor T cell exclusion and overcomes cancer immunotherapy resistance.

T cell exclusion causes resistance to cancer immunotherapies via immune checkpoint blockade (ICB). Myeloid cells contribute to resistance by expressing signal regulatory protein-α (SIRPα), an inhibitory membrane receptor that interacts with ubiquitous receptor CD47 to control macrophage phagocytosis in the tumor microenvironment. Although CD47/SIRPα-targeting drugs have been assessed in preclinical models, the therapeutic benefit of selectively blocking SIRPα, and not SIRPγ/CD47, in humans remains unknown. We report a potent synergy between selective SIRPα blockade and ICB in increasing memory T cell responses and reverting exclusion in syngeneic and orthotopic tumor models. Selective SIRPα blockade stimulated tumor nest T cell recruitment by restoring murine and human macrophage chemokine secretion and increased anti-tumor T cell responses by promoting tumor-antigen crosspresentation by dendritic cells. However, nonselective SIRPα/SIRPγ blockade targeting CD47 impaired human T cell activation, proliferation, and endothelial transmigration. Selective SIRPα inhibition opens an attractive avenue to overcoming ICB resistance in patients with elevated myeloid cell infiltration in solid tumors.

Sufrimiento psicológico en hombres y mujeres con síntomas de depresión / Psychological suffering in men and women with symptoms of depression

Resumen El objetivo del presente estudio descriptivo comparativo era determinar si existían diferencias en la expresión de sufrimiento psicológico en una muestra de 269 personas con edades entre los 18 y 58 años (M= 31.2), distribuidas en 4 grupos de acuerdo con el sexo y el reporte o no de síntomas de depresión. Para evaluar sufrimiento se utilizó la Entrevista de Percepción del Paso del Tiempo, el Cuestionario de Depresión de Hombres, la Escala Zung de Depresión para las mujeres y la Escala de Salud Mental Self Reporting Questionare (SRQ). Se utilizó el estadístico ANOVA para determinar la diferencia de medias y un análisis pos hoc para identificar la dirección de la diferencia. Los resultados indican que, aunque las mujeres reportaron puntajes más altos en la escala de depresión, los hombres reportan significativamente más sufrimiento psicológico, y que este es independiente del reporte del puntaje de depresión obtenido.

Abstract The hardiness is a variable of great importance in the protection of health, so the validation and adaptation of instruments to evaluate it are necessary. The objective of the research was to evaluate the psychometric properties of the Hardiness Questionnaire (non-work version) for a sample of the Cuban population. An instrumental study was carried out based on the quantitative research paradigm. The sample selection was made based on a cluster sampling that included 400 subjects residing in six provinces of the country. The standard age chosen was 48 (±14.7) ; 54.5 % of the simple was for females. Three models were estimated, the one who showed better scores was the trifactorial one (control, implication and challenge) with a factor of a second order (hardiness) reduced from the elimination of two reactive. Some acceptable figures of reliability were obtained, both global (a=0.83) and as in each dimension: control and challenge (a=0.77) and implication (a=0.70). The recurrent validity brings evidence of the value of the subscales control and commitment.

Words hurt: Political rhetoric, emotions/affect, and psychological well-being among Mexican-origin youth.

We examined the effect of political rhetoric on the targets of that rhetoric. Drawing from scholarship on anti-Mexican and anti-immigrant rhetoric found readily in various media and scholarship on emotions, we tested four hypotheses. Hypotheses 1 and 2 predicted that positive and negative political rhetoric would increase and decrease positive and negative emotions, respectively. Hypotheses 3 and 4 then predicted that emotional responses to positive or negative political rhetoric would influence perceived stress, subjective health, and subjective well-being. Data collection occurred between August 2016 and June 2017 at a university in California. A sample of 280 Mexican-origin youth, defined broadly as having at least one ancestor born in Mexico or the participant themselves born in Mexico, participated in an experiment where they were randomly assigned to one of three study conditions: viewing (1) positive or (2) negative political rhetoric about immigrants and Latinos in general, or (3) neutral rhetoric as a control condition before providing qualitative responses to open-ended questions and completing measures of positive and negative affect, perceived stress, subjective health, and subjective well-being. Qualitative responses indicated that negative and positive political rhetoric elicited a range of negative emotions and positive emotions, respectively. Quantitative analysis with independent samples t-tests, ANOVA, and linear regression models found that negative political rhetoric elicited higher negative affect than positive and neutral rhetoric, and positive rhetoric elicited higher positive affect than negative and neutral rhetoric. Negative emotional responses, in turn, were associated with participants' higher perceived stress, lower subjective health and lower subjective well-being. Conversely, positive emotional responses were associated with lower perceived stress, higher subjective health, and higher subjective well-being. Positive political rhetoric, by eliciting positive emotions, can have a salubrious effect. Altogether, these findings suggest that political rhetoric matters for the targets of that rhetoric.

Burn Rehabilitation Therapists Competency Tool-Version 2: An Expansion to Include Long-Term Rehabilitation and Outpatient Care.

The Burn Rehabilitation Therapist Competency Tool (BRTCT) was developed in 2011 to define core knowledge and skill sets that are central to the job performance of occupational and physical therapists working with burn patients during acute hospitalization and initial rehabilitation. It was the first national effort to provide standards that burn centers could use for the training and evaluation of a BRT performance. The American Burn Association Rehabilitation Committee recently expanded the tool to include long-term rehabilitation and outpatient care in order to more fully represent all of the stages of care in which patients with burn injury receive therapy. Thirty-six burn centers contributed competencies, 17 rehabilitation experts participated in a systematic Delphi questionnaire process, and eight representatives from seven additional burn centers validated the tool. The revised BRTCT, called the BRTCT-2, includes four new practice domains and 28 new competency statements. The expanded tool provides a common framework of standards for performance for occupational and physical therapists working with patients throughout the full spectrum of burn care.

Perturbations of the CD8(+) T-cell repertoire in CVID patients with complications.

A higher chronic expansion of effector cytotoxic CD8(+)DR(+) T-lymphocytes has been reported in common variable immunodeficiency (CVID) patients with complications such as splenomegaly, autoimmune disease and/or granulomatous disease. In order to document the features associated with this T cell activation involving the CD8(+) T-compartment, we examined the diversity of the alpha/beta TCR repertoire of the patient's CD8(+) T-lymphocytes using the qualitative analysis of the CDR3 lengths (Immunoscope). Ten CIVD patients were enrolled in this study, four without complications (Group 1), six with complications (Group 2). All patients exhibited non-gaussian altered CDR3 length distributions, albeit to different extent within the different Vß families. CVID patients with activated CD8(+) T-cells show a reduction of their TCR repertoire diversity which is more severe in patients with complications. Viral reactivations such as CMV are suspected to be part of the mechanisms underlying immunosenescence.

Analysis of the peripheral T-cell repertoire in kidney transplant patients.

The long-term stability of renal grafts depends on the absence of chronic rejection. As T cells play a key role in rejection processes, analyzing the T-cell repertoire may be useful for understanding graft function outcomes. We have therefore investigated the power of a new statistical tool, used to analyze the peripheral blood TCR repertoire, for determining immunological differences in a group of 229 stable renal transplant patients undergoing immunosuppression. Despite selecting the patients according to stringent criteria, the patients displayed heterogeneous T-cell repertoire usage, ranging from unbiased to highly selected TCR repertoires; a skewed TCR repertoire correlating with an increase in the CD8(+) /CD4(+) T-cell ratio. T-cell repertoire patterns were compared in patients with clinically opposing outcomes i.e. stable drug-free operationally tolerant recipients and patients with the "suspicious" form of humoral chronic rejection and were found significantly different, from polyclonal to highly selected TCR repertoires, respectively. Moreover, a selected TCR repertoire was found to positively correlate with the Banff score grade. Collectively, these data suggest that TCR repertoire categorization might be included in the calculation of a composite score for the follow-up of patients after kidney transplantation.

Identification of a peripheral blood transcriptional biomarker panel associated with operational renal allograft tolerance.

Long-term allograft survival generally requires lifelong immunosuppression (IS). Rarely, recipients display spontaneous "operational tolerance" with stable graft function in the absence of IS. The lack of biological markers of this phenomenon precludes identification of potentially tolerant patients in which IS could be tapered and hinders the development of new tolerance-inducing strategies. The objective of this study was to identify minimally invasive blood biomarkers for operational tolerance and use these biomarkers to determine the frequency of this state in immunosuppressed patients with stable graft function. Blood gene expression profiles from 75 renal-transplant patient cohorts (operational tolerance/acute and chronic rejection/stable graft function on IS) and 16 healthy individuals were analyzed. A subset of samples was used for microarray analysis where three-class comparison of the different groups of patients identified a "tolerant footprint" of 49 genes. These biomarkers were applied for prediction of operational tolerance by microarray and real-time PCR in independent test groups. Thirty-three of 49 genes correctly segregated tolerance and chronic rejection phenotypes with 99% and 86% specificity. The signature is shared with 1 of 12 and 5 of 10 stable patients on triple IS and low-dose steroid monotherapy, respectively. The gene signature suggests a pattern of reduced costimulatory signaling, immune quiescence, apoptosis, and memory T cell responses. This study identifies in the blood of kidney recipients a set of genes associated with operational tolerance that may have utility as a minimally invasive monitoring tool for guiding IS titration. Further validation of this tool for safe IS minimization in prospective clinical trials is warranted.

Serial evolution of TCR beta chain transcript mobilization in HIV type-1-infected patients following vaccine immune stimulation and HAART interruption.

In this article, we studied the T cell receptor (TCR)beta chain transcript mobilization in peripheral blood lymphocytes harvested from HIV-1-infected patients before and after vaccination with a mixture of six lipopeptides and at the moment and serially after highly active antiretroviral therapy (HAART) interruption. This study was performed by using a combined qualitative and quantitative assessment of Vbeta mRNA alterations at the level of complementary determining region 3 length distribution (CDR3-LD) of the TCR. Whereas healthy individuals displayed both stable CDR3-LD profiles and Vbeta transcript accumulations over time, the four HIV-1-infected patients in a quiescent disease phase under HAART have a highly significantly biased CDR3-LD. In addition, they displayed a significant further increase of alterations of their beta CDR3-LD profile after vaccination and both a more altered CDR3-LD (p < 0.05) and an increased transcript accumulation of some Vbeta families after HAART interruption. These modifications mostly concerned the CD8(+ve) T cells. Such a global approach of TCR alterations may help to follow the immune response of these patients and allow targeting of more complex in vivo studies by identifying the T cells with a selected repertoire.

Serial blood T cell repertoire alterations in multiple sclerosis patients; correlation with clinical and MRI parameters.

A significant skewing of the peripheral T cell repertoire has been shown in relapsing-remitting multiple sclerosis (MS). Most of the studies already performed in this field are cross-sectional and therefore, little is known of the T cell repertoire evolution over time in MS and the correlation of T cell repertoire variation with clinical and MRI parameters. This study was performed on serially harvested frozen PBMC from nine untreated MS patients (27 samples) and 14 healthy individuals. The blood T cell repertoire of each patient was analysed at the complementarity determining region 3 (CDR3) level and compared with a monthly MRI scan performed over a six month period with assessment of T2 lesion load and gadolinium enhancing lesions. A highly significant blood T cell repertoire skewing was observed in MS patients as compared with healthy controls (p<0.01). In addition, the number of altered Vbeta families correlated significantly with both the T2 lesion volume and the number of gadolinium enhancing lesions as assessed by MRI (Spearman correlation tests, r=0.51 and r=0.44, p<0.01 and p<0.05 respectively). Furthermore, the variation of the number of altered Vbeta families over time also correlated with the appearance of new gadolinium enhancing lesions (r=0.36, p=0.05). These findings which need confirmation on larger serial cohorts, suggest an association between the magnitude of TCRBV CDR3 length distribution alterations in the peripheral blood of MS patients and the disease process.

Operationally tolerant and minimally immunosuppressed kidney recipients display strongly altered blood T-cell clonal regulation.

Most kidney transplant recipients who discontinue immunosuppression reject their graft. Nevertheless, a small number do not, suggesting that allogeneic tolerance state (referred to operational tolerance) is achievable in humans. So far, however, the rarity of such patients has limited their study. Because operational tolerance could be linked to anergy, ignorance or to an active regulatory mechanism, we analyzed the blood T-cell repertoire usage of these patients. We report on comparison of T-cell selection in drug-free operationally tolerant kidney recipients (or with minimal immunosuppression), recipients with stable graft function, chronic rejection and healthy individuals. The blood T cells of operationally tolerant patients display two major characteristics: an unexpected strongly altered T-cell receptor (TCR) Vbeta usage and high TCR transcript accumulation in selected T cells. The cytokine transcriptional patterns of sorted T cells with altered TCR usage show no accumulation of cytokine transcripts (IL10, IL2, IL13, IFN-gamma), suggesting a state of hyporesponsiveness in these patients. Identification of such a potential surrogate pattern of operational tolerance in transplant recipients under life-long immunosuppression may provide a new basis and rationale for exploration of tolerance state. However, these data obtained in a limited number of patients require further confirmation on larger series.

Blood T-cell Vbeta transcriptome in melanoma patients.

Tumor-cells have been shown to elicit MHC-restricted and antigen-specific T-cell responses. In this article, we used a new approach to study T-cell responses in tumor-bearing patients based on a global representation of the Vbeta-transcriptome, making it possible to grade CDR3-length distribution (CDR3-LD) alterations. Six patients with advanced melanoma disease, from whom blood samples were taken before and serially after tyrosinase-A peptide vaccination, were studied. The PBMC from patients displayed highly significant Vbeta transcriptome alterations as compared to healthy individuals. Similar Vbeta alterations could be detected both in PBMCs and at the tumor site. After vaccination, Vbeta alterations could also be observed by gauging individually their transcript level but not their cell-surface expression. Some Vbeta families exhibited high Vbeta/HPRT transcript ratios (e.g., Vbeta1), which represented up to 44% of the whole transcriptome, a situation that was not reflected by an increase in the percentage of T cells that expressed the corresponding protein and was not observed in normal individuals. In several instances, CDR3-LD altered T cells exhibited MHC-restricted and tumor-specific IFNgamma or GM-CSF production. Finally, we show that the presence of a tumor and probably vaccination can affect Vbeta transcriptome patterns and induce specific clones reactive to autologous tumor or vaccinating peptides. In combination with other methods, such an approach should help in identifying the clones actually involved in the response against the tumor.

Blood T-cell receptor beta chain transcriptome in multiple sclerosis. Characterization of the T cells with altered CDR3 length distribution.

Multiple sclerosis is an inflammatory demyelinating disease of the CNS associated with T cells autoreactive for myelin components. In this study, we analysed the T-cell receptor (TCR) usage of the variable beta (Vbeta) chain transcriptome in the blood of multiple sclerosis patients at various stages of the disease using a global and quantitative comparison of the complementarity-determining region 3 length distribution (CDR3-LD) of transcripts of the 26 Vbeta genes. We investigated 35 patients: 12 with a high risk of multiple sclerosis, 10 with clinically definite multiple sclerosis, 13 with a relapsing-remitting worsening and active multiple sclerosis and 13 healthy individuals. Cells bearing the TCR transcripts with altered CDR3-LD were sorted and studied for CD4 or CD8 phenotype, cytokine transcript accumulation and response to human myelin basic protein (MBP). We show that patients from all the groups have a significantly skewed blood T-cell repertoire. Vbeta transcriptome patterns were more altered in patients from the clinically definite multiple sclerosis group and the worsening and active multiple sclerosis group than in the high risk group. The T cells sorted from Vbeta families with altered CDR3-LD concerned both CD4 and CD8 T cells, with a more pronounced skewing in the CD8 compartment. These cells displayed a significantly increased level of interferon-gamma, interleukin-2 and tumour necrosis factor-alpha transcripts compared with their counterparts from the healthy individual group. Furthermore, using interferon-gamma enzyme-linked immunospot (ELISPOT) assays, T cells from four out of seven altered Vbeta families tested from multiple sclerosis patients responded to human MBP, whereas no response was observed with human albumin or with altered Vbeta families from healthy individuals. Our data support the concept of an early autoimmune component in the disease and emphasize the possible involvement of CD8-positive T cells in multiple sclerosis.