Postal screening can identify frailty and predict poor outcomes in older adults: longitudinal data from INTER-FRAIL study.

OBJECTIVE: identification of older individuals at risk for health-related adverse outcomes (HRAO) is necessary for population-based preventive interventions. Aim of this study was to improve a previously validated postal screening questionnaire for frailty in non-disabled older subjects and to test its prognostic validity in a vast sample of older community-dwellers. METHODS: individuals aged 70+ underwent a mass postal screening. Physical frailty phenotype (PFP) was assessed in the unselected subsample of the first responders. After a 1-year follow-up, HRAO were recorded in the whole sample, including survival, access to Emergency Department, hospitalisation and Long-Term Care admission. RESULTS: the questionnaire was mailed to 17,273 subjects, whose response rate was 55%. Among the first 1,037 responders without overt disability, the revised questionnaire was 75% sensitive and 69% specific for PFP (ROC 0.772). Non-disabled subjects who screened positive had a higher risk of HRAO in comparison with those who screened negative and similar to non-responders. Risk of adverse outcome was highest among disabled subjects. CONCLUSIONS: a simple questionnaire delivered by mail has good accuracy in detecting PFP in non-disabled older subjects and is able to predict HRAO.

Assessing the implications of sentinel lymph node removal in cervical cancer: an immunogenetic perspective - a SENTICOL ancillary study.

BACKGROUND: Cervical cancer's lymphatic spread primarily begins from the sentinel lymph nodes (SLNs), underlining their pivotal role in disease metastasis. However, these nodes' immune gene expression profiles and immunoregulation mechanisms have yet to be explored. METHODS: Our study aimed to elucidate the immune cell populations and their roles in the immune gene expression profile of negative SLNs compared with positive SLNs and non-SLNs using Nanostring RNA seq analysis. We performed a principal component analysis on the log2 normalized expression of 685 endogenous genes in the nCounter PanCancer Immune Profiling Panel, followed by an assessment of the differential expression of genes and immune cell type abundance. RESULTS: We found significant variations in gene expression among the groups, with negative SLNs displaying overexpression of genes related to tumor-infiltrating immune cells, specifically innate cell populations. They also demonstrated the upregulation of genes involved in antigen presentation and T-cell priming. In contrast, positive SLNs were enriched in regulatory networks, suggesting their potential role in immune evasion. A comparison of negative SLNs and non-SLNs revealed increased innate and adaptive immune cell types, underscoring the ongoing T cell response to tumor antigens. CONCLUSION: Our findings underscore a specific immunogenetic phenotype profile in negative SLNs, emphasizing their crucial role in the initial anticancer response, immunosurveillance, and the propagation of immune tolerance from the primary cervical tumor. These results highlight the potential of SLNs as a novel target for immunotherapy strategies and underscore the importance of new imaging methods for accurately identifying SLN status without removal. Future investigations are needed to understand further the immunological interplay within SLNs and their influence on cervical cancer progression.

[A screening and comprehensive assessment programme aimed at secondary prevention of disability in community-dwelling frail older subjects: a pilot study]. / Screening della fragilità e valutazione multidimensionale degli anziani residenti a domicilio per la prevenzione secondaria della disabilità: risultati di uno studio pilota.

OBJECTIVE: to test a screening and comprehensive assessment procedures for frail elderly in Tuscany (Central Italy) in the perspective of interventions to prevent disability. DESIGN: two-phases feasibility study: a) screening phase, using a postal questionnaire and b) comprehensive assessment phase, aimed at identifying risk factors for disability that might be targeted by specific interventions. SETTING AND PARTICIPANTS: 11,589 individuals aged over 70, living at home, identified from residents registry of 2 health care districts in Tuscany, excluding subjects with recognized disability and those living in nursing home. Participants were sent a 7-item postal questionnaire (modified Sherbrooke Postal Questionnaire). Respondents with a score =3, suggestive of frailty, were offered an in-home comprehensive assessment performed by a nurse or social worker, oriented to ascertain independence in activities of daily living, lower limbs extremity function, mood status, malnutrition risk, cognitive level, visual acuity, hearing function, environmental risk and medications number. General practitioners, social workers or specific health care services were thereafter informed about results of the assessment with recommendations for specific interventions. RESULTS: among 6,629 respondents to the questionnaire, 52% (No. 3,432) scored =3, triggering the comprehensive assessment, which was performed in 66% of cases (No. 2,276). Out of them, 38% showed already a disability in basic activities of daily living. Of the remaining 1,411, 38% showed a disability in instrumental activities of daily living, 30% a reduced lower limb extremity function, 18% depressive symptoms, and 11% a cognitive impairment. Human resources used for the project were limited in relation to the extent of the involved population. CONCLUSIONS: postal screening of frailty in older subjects is feasible and is able to identify patients who might benefit from further assessment to address interventions for specific risk factors.

Distant antimetastatic effect of enterotropic colon cancer-derived α4ß7+CD8+ T cells.

Despite the high prognostic value of immune infiltrates in colorectal cancer (CRC), metastatic disease remains resistant to immunotherapy by immune checkpoint blockade (ICB). Here, we show, in metastatic CRC preclinical models, that orthotopically implanted primary colon tumors exert a colon-specific antimetastatic effect on distant hepatic lesions. Enterotropic α4ß7 integrin-expressing neoantigen-specific CD8 T cells were key components of the antimetastatic effect. Accordingly, the presence of concomitant colon tumors improved control of liver lesions by anti-PD-L1 proof-of-concept immunotherapy and generated protective immune memory, whereas partial depletion of α4ß7+ cells abrogated control of metastases. Last, in patients with metastatic CRC, response to ICB was associated with expression of α4ß7 integrin in metastases and with circulating α4ß7+ CD8 T cells. Our findings identify a systemic cancer immunosurveillance role for gut-primed tumor-specific α4ß7+ CD8 T cells.

Circulating Exhausted PD-1+CD39+ Helper CD4 T Cells Are Tumor-Antigen-Specific and Predict Response to PD-1/PD-L1 Axis Blockade.

Tumor-infiltrating exhausted PD-1hiCD39+ tumor-antigen (Ag)-specific CD4 T cells contribute to the response to immune checkpoint blockade (ICB), but their circulating counterparts, which could represent accessible biomarkers, have not been assessed. Here, we analyzed circulating PD-1+CD39+ CD4 T cells and show that this population was present at higher proportions in cancer patients than in healthy individuals and was enriched in activated HLA-DR+ and ICOS+ and proliferating KI67+ cells, indicative of their involvement in ongoing immune responses. Among memory CD4 T cells, this population contained the lowest proportions of cells producing effector cytokines, suggesting they were exhausted. In patients with HPV-induced malignancies, the PD-1+CD39+ population contained high proportions of HPV Ag-specific T cells. In patients treated by ICB for HPV-induced tumors, the proportion of circulating PD-1+CD39+ CD4 T cells was predictive of the clinical response. Our results identify CD39 expression as a surrogate marker of circulating helper tumor-Ag-specific CD4 T cells.

PD-1 blockade restores helper activity of tumor-infiltrating, exhausted PD-1hiCD39+ CD4 T cells.

Tumor antigen-specific CD4 T cells accumulate at tumor sites, evoking their involvement in antitumor effector functions in situ. Contrary to CD8 cytotoxic T lymphocyte exhaustion, that of CD4 T cells remains poorly appreciated. Here, using phenotypic, transcriptomic, and functional approaches, we characterized CD4 T cell exhaustion in patients with head and neck, cervical, and ovarian cancer. We identified a CD4 tumor-infiltrating lymphocyte (TIL) population, defined by high PD-1 and CD39 expression, which contained high proportions of cytokine-producing cells, although the quantity of cytokines produced by these cells was low, evoking an exhausted state. Terminal exhaustion of CD4 TILs was instated regardless of TIM-3 expression, suggesting divergence with CD8 T cell exhaustion. scRNA-Seq and further phenotypic analyses uncovered similarities with the CD8 T cell exhaustion program. In particular, PD-1hiCD39+ CD4 TILs expressed the exhaustion transcription factor TOX and the chemokine CXCL13 and were tumor antigen specific. In vitro, PD-1 blockade enhanced CD4 TIL activation, as evidenced by increased CD154 expression and cytokine secretion, leading to improved dendritic cell maturation and consequently higher tumor-specific CD8 T cell proliferation. Our data identify exhausted CD4 TILs as players in responsiveness to immune checkpoint blockade.

A Virus Hosted in Malaria-Infected Blood Protects against T Cell-Mediated Inflammatory Diseases by Impairing DC Function in a Type I IFN-Dependent Manner.

Coinfections shape immunity and influence the development of inflammatory diseases, resulting in detrimental or beneficial outcome. Coinfections with concurrent Plasmodium species can alter malaria clinical evolution, and malaria infection itself can modulate autoimmune reactions. Yet, the underlying mechanisms remain ill defined. Here, we demonstrate that the protective effects of some rodent malaria strains on T cell-mediated inflammatory pathologies are due to an RNA virus cohosted in malaria-parasitized blood. We show that live and extracts of blood parasitized by Plasmodium berghei K173 or Plasmodium yoelii 17X YM, protect against P. berghei ANKA-induced experimental cerebral malaria (ECM) and myelin oligodendrocyte glycoprotein (MOG)/complete Freund's adjuvant (CFA)-induced experimental autoimmune encephalomyelitis (EAE), and that protection is associated with a strong type I interferon (IFN-I) signature. We detected the presence of the RNA virus lactate dehydrogenase-elevating virus (LDV) in the protective Plasmodium stabilates and we established that LDV infection alone was necessary and sufficient to recapitulate the protective effects on ECM and EAE. In ECM, protection resulted from an IFN-I-mediated reduction in the abundance of splenic conventional dendritic cell and impairment of their ability to produce interleukin (IL)-12p70, leading to a decrease in pathogenic CD4+ Th1 responses. In EAE, LDV infection induced IFN-I-mediated abrogation of IL-23, thereby preventing the differentiation of granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing encephalitogenic CD4+ T cells. Our work identifies a virus cohosted in several Plasmodium stabilates across the community and deciphers its major consequences on the host immune system. More generally, our data emphasize the importance of considering contemporaneous infections for the understanding of malaria-associated and autoimmune diseases.IMPORTANCE Any infection modifies the host immune status, potentially ameliorating or aggravating the pathophysiology of a simultaneous inflammatory condition. In the course of investigating how malaria infection modulates the severity of contemporaneous inflammatory diseases, we identified a nonpathogenic mouse virus in stabilates of two widely used rodent parasite lines: Plasmodium berghei K173 and Plasmodium yoelii 17X YM. We established that the protective effects of these Plasmodium lines on cerebral malaria and multiple sclerosis are exclusively due to this virus. The virus induces a massive type I interferon (IFN-I) response and causes quantitative and qualitative defects in the ability of dendritic cells to promote pathogenic T cell responses. Beyond revealing a possible confounding factor in rodent malaria models, our work uncovers some bases by which a seemingly innocuous viral (co)infection profoundly changes the immunopathophysiology of inflammatory diseases.

Robust Control of a Brain-Persisting Parasite through MHC I Presentation by Infected Neurons.

Control of CNS pathogens by CD8 T cells is key to avoid fatal neuroinflammation. Yet, the modalities of MHC I presentation in the brain are poorly understood. Here, we analyze the antigen presentation mechanisms underlying CD8 T cell-mediated control of the Toxoplasma gondii parasite in the CNS. We show that MHC I presentation of an efficiently processed model antigen (GRA6-OVA), even when not expressed in the bradyzoite stage, reduces cyst burden and dampens encephalitis in C57BL/6 mice. Antigen presentation assays with infected primary neurons reveal a correlation between lower MHC I presentation of tachyzoite antigens by neurons and poor parasite control in vivo. Using conditional MHC I-deficient mice, we find that neuronal MHC I presentation is required for robust restriction of T. gondii in the CNS during chronic phase, showing the importance of MHC I presentation by CNS neurons in the control of a prevalent brain pathogen.

Profiling MHC II immunopeptidome of blood-stage malaria reveals that cDC1 control the functionality of parasite-specific CD4 T cells.

In malaria, CD4 Th1 and T follicular helper (TFH) cells are important for controlling parasite growth, but Th1 cells also contribute to immunopathology. Moreover, various regulatory CD4 T-cell subsets are critical to hamper pathology. Yet the antigen-presenting cells controlling Th functionality, as well as the antigens recognized by CD4 T cells, are largely unknown. Here, we characterize the MHC II immunopeptidome presented by DC during blood-stage malaria in mice. We establish the immunodominance hierarchy of 14 MHC II ligands derived from conserved parasite proteins. Immunodominance is shaped differently whether blood stage is preceded or not by liver stage, but the same ETRAMP-specific dominant response develops in both contexts. In naïve mice and at the onset of cerebral malaria, CD8α+ dendritic cells (cDC1) are superior to other DC subsets for MHC II presentation of the ETRAMP epitope. Using in vivo depletion of cDC1, we show that cDC1 promote parasite-specific Th1 cells and inhibit the development of IL-10+ CD4 T cells. This work profiles the P. berghei blood-stage MHC II immunopeptidome, highlights the potency of cDC1 to present malaria antigens on MHC II, and reveals a major role for cDC1 in regulating malaria-specific CD4 T-cell responses.

Screening for frailty in older adults using a postal questionnaire: rationale, methods, and instruments validation of the INTER-FRAIL study.

OBJECTIVES: To develop and test a postal screening questionnaire to intercept frailty in older community-dwelling individuals. DESIGN: A questionnaire was developed on the basis of expert consensus and preliminarily tested against the occurrence of incident disability, in secondary analyses of previous epidemiological studies. The questionnaire was then mailed and its concurrent validity, defined from the association between its individual items and summary score and the presence of the Fried frailty phenotype (FFP), was subsequently evaluated cross-sectionally with in-person examination of initial participants. SETTING: Community-based. PARTICIPANTS: Individuals aged 70 and older living in two communities near Florence, Italy. MEASUREMENTS: A home comprehensive geriatric assessment including the FFP was conducted in participants who screened positive for frailty and in a limited sample of negative responders. RESULTS: A 10-item questionnaire, developed based on expert consensus, was preliminarily tested on preexisting epidemiological data and showed an area under the receiver operating characteristic curve (AUC) of 0.716 versus incident disability. The questionnaire was then mailed to 15,774 subjects, whose response rate was 53.6%. Of the first 1,037 participants included in the concurrent validation study, 833 (80.3%) screened positive, and 380 (36.6%) were frail on assessment. The ability of the questionnaire summary score to predict frailty was adequate, with an AUC of 0.695, a sensitivity of 71%, and a specificity of 58%. CONCLUSION: A simple questionnaire delivered by mail was able to identify FFP in the community. This would facilitate large-scale screening for frailty in older persons.