Biology subjects

Alanio, C.

Publications and source records attributed to Alanio, C..

7 recordsLinked to original sources

bioRxiv2026

Integration of clinical and T-cell immune profiling to predict early response to CD3xBCMA bispecific antibody immunotherapy in Multiple Myeloma

The emergence of bispecific antibodies (BsAbs) targeting T cells (CD3+) and tumor plasma B cells (BCMA+) has provided a new therapeutic option for patients with relapsed/refractory multiple myeloma cancer. However, responses to CD3xBCMA BsAb therapy remain heterogeneous, and treatment is associated with frequent immune-related adverse events. Although baseline immune characteristics have been associated with clinical outcomes, little is known about the early immune dynamics induced by this therapy. Here, we investigated whether longitudinal clinical monitoring and high-dimensional profiling of blood circulating T cells could identify early biomarkers of response or toxicity during treatment. Our results indicate that all treated patients exhibit an early depletion of circulating T cells associated with T-cell activation within the first two weeks. Integration of clinical and immunological parameters using Factorial Analysis of Mixed Data (FAMD) identified immune features associated with treatment outcome. Responders had lower plasma soluble BCMA concentrations, fewer bone lesions, higher circulating lymphocyte counts at baseline. During the first days of treatment, responders exhibited a more pronounced increase in plasma CXCL10 levels, associated with a greater decrease in T lymphocyte counts. Overall, our findings suggest that integrating clinical and immune parameters measured during the first days of treatment may enable early patient stratification and support the development of a predictive score to identify patients with multiple myeloma who are most likely to benefit from CD3xBCMA BsAb therapy. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=94 SRC="FIGDIR/small/743749v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@1cb079org.highwire.dtl.DTLVardef@1860106org.highwire.dtl.DTLVardef@ad36d3org.highwire.dtl.DTLVardef@1ea5c1e_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIIntegrated clinical and blood T-cell immune profiling using FAMD enables patient stratification following CD3xBCMA BsAb therapy. C_LIO_LIT-cell immune activation occurs predominantly within the first two weeks of therapy. C_LIO_LIFirst-week clinical and immune parameters identify patients most likely to benefit from therapy. C_LIO_LIHigh CXCL10 levels, a profound early decline in circulating T cells, low sBCMA levels, and fewer bone lesions are candidate predictive markers of treatment response. C_LI

immunology↗

bioRxiv2021

Decade-long remissions of leukemia sustained by the persistence of activated CD4+ CAR T-cells

The adoptive transfer of T lymphocytes reprogrammed to target tumor cells has demonstrated significant potential in various malignancies. However, little is known about the long-term potential and the clonal stability of the infused cells. Here, we studied the longest persisting CD19-redirected chimeric antigen receptor (CAR) T cells to date in two chronic lymphocytic leukemia (CLL) patients who achieved a complete remission in 2010. CAR T-cells were still detectable up to 10+ years post-infusion, with sustained remission in both patients. Surprisingly, a prominent, highly activated CD4+ population developed in both patients during the years post-infusion, dominating the CAR T-cell population at the late time points. This transition was reflected in the stabilization of the clonal make-up of CAR T-cells with a repertoire dominated by few clones. Single cell multi-omics profiling via Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-Seq) with TCR sequencing of CAR T-cells obtained 9.3 years post-infusion demonstrated that these long-persisting CD4+ CAR T-cells exhibited cytotoxic characteristics along with strong evidence of ongoing functional activation and proliferation. Our data provide novel insight into the CAR T-cell characteristics associated with long-term remission in leukemia.

immunology↗

bioRxiv2021

Signaling through FcγRIIA and the C5a-C5aR pathway mediates platelet hyperactivation in COVID-19

Patients with COVID-19 present with a wide variety of clinical manifestations. Thromboembolic events constitute a significant cause of morbidity and mortality in patients infected with SARS-CoV-2. Severe COVID-19 has been associated with hyperinflammation and pre-existing cardiovascular disease. Platelets are important mediators and sensors of inflammation and are directly affected by cardiovascular stressors. In this report, we found that platelets from severely ill, hospitalized COVID-19 patients exhibit higher basal levels of activation measured by P-selectin surface expression, and have a poor functional reserve upon in vitro stimulation. Correlating clinical features to the ability of plasma from COVID-19 patients to stimulate control platelets identified ferritin as a pivotal clinical marker associated with platelet hyperactivation. The COVID-19 plasma-mediated effect on control platelets was highest for patients that subsequently developed inpatient thrombotic events. Proteomic analysis of plasma from COVID-19 patients identified key mediators of inflammation and cardiovascular disease that positively correlated with in vitro platelet activation. Mechanistically, blocking the signaling of the Fc{gamma}RIIa-Syk and C5a-C5aR pathways on platelets, using antibody-mediated neutralization, IgG depletion or the Syk inhibitor fostamatinib, reversed this hyperactivity driven by COVID-19 plasma and prevented platelet aggregation in endothelial microfluidic chamber conditions, thus identifying these potentially actionable pathways as central for platelet activation and/or vascular complications in COVID-19 patients. In conclusion, we reveal a key role of platelet-mediated immunothrombosis in COVID-19 and identify distinct, clinically relevant, targetable signaling pathways that mediate this effect. These studies have implications for the role of platelet hyperactivation in complications associated with SARS-CoV-2 infection. Cover illustration O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY One-sentence summaryThe Fc{gamma}RIIA and C5a-C5aR pathways mediate platelet hyperactivation in COVID-19

immunology↗

bioRxiv2020

Deep immune profiling of COVID-19 patients reveals patient heterogeneity and distinct immunotypes with implications for therapeutic interventions

COVID-19 has become a global pandemic. Immune dysregulation has been implicated, but immune responses remain poorly understood. We analyzed 71 COVID-19 patients compared to recovered and healthy subjects using high dimensional cytometry. Integrated analysis of [~]200 immune and >30 clinical features revealed activation of T cell and B cell subsets, but only in some patients. A subgroup of patients had T cell activation characteristic of acute viral infection and plasmablast responses could reach >30% of circulating B cells. However, another subgroup had lymphocyte activation comparable to uninfected subjects. Stable versus dynamic immunological signatures were identified and linked to trajectories of disease severity change. These analyses identified three "immunotypes" associated with poor clinical trajectories versus improving health. These immunotypes may have implications for therapeutics and vaccines.

immunology↗

bioRxiv2019

Vaccine-induced ICOS+CD38+ cTfh are sensitive biosensors of age-related changes in inflammatory pathways

Humoral immune responses are dysregulated with aging but details remain incompletely understood. In particular, little is known about the effects of aging on T follicular helper (Tfh) CD4 cells, the subset that provides critical help to B cells for effective humoral immunity. We previously demonstrated that influenza vaccination increases a circulating Tfh (cTfh) subset that expresses ICOS and CD38, contains influenza-specific memory cells, and is correlated with antibody responses. To directly study the effects of aging on the cTfh response, we performed transcriptional profiling and cellular analysis before and after influenza vaccination in young and elderly adults. Several key differences in cTfh responses were revealed in the elderly. First, whole blood transcriptional profiling defined cross-validated genesets of youth versus aging and these genesets were, compared to other T cells, preferentially enriched in ICOS+CD38+ cTfh from young and elderly subjects, respectively, following vaccination. Second, vaccine-induced ICOS+CD38+ cTfh from the elderly were enriched for transcriptional signatures of inflammation including TNF-NFkB pathway activation. Indeed, we reveal a paradoxical positive effect of TNF signaling on Tfh providing help to B cells linked to survival circuits that may explain detrimental effects of TNF blockade on vaccine responses. Finally, vaccine-induced ICOS+CD38+ cTfh displayed strong enrichment for signatures of underlying age-associated biological changes. Thus, these data reveal key biological changes in cTfh during aging and also demonstrate the sensitivity of vaccine-induced cTfh to underlying changes in host physiology. This latter observation suggests that vaccine-induced cTfh could function as sensitive biosensors of underlying inflammatory and/or overall immune health.\n\nOne sentence summaryTranscriptional profiling of vaccine-induced circulating T follicular helper cell responding to influenza vaccination reveals age-associated effects on Tfh such as alterations in TNF-NFkB signaling.

immunology↗

bioRxiv2019

A Comprehensive Assessment of Demographic, Environmental and Host Genetic Associations with Gut Microbiome Diversity in Healthy Individuals

BackgroundThe gut microbiome is an important determinant of human health. Its composition has been shown to be influenced by multiple environmental factors and likely by host genetic variation. In the framework of the Milieu Interieur Consortium, a total of 1,000 healthy individuals of western European ancestry, with a 1:1 sex ratio and evenly stratified across five decades of life (age 20 - 69), were recruited. We generated 16S ribosomal RNA profiles from stool samples for 858 participants. We investigated genetic and non-genetic factors that contribute to individual differences in fecal microbiome composition. ResultsAmong 110 demographic, clinical and environmental factors, 11 were identified as significantly correlated with -diversity, {beta}-diversity or abundance of specific microbial communities in multivariable models. Age and blood alanine aminotransferase levels showed the strongest associations with microbiome diversity. In total, all non-genetic factors explained 16.4% of the variance. We then searched for associations between >5 million single nucleotide polymorphisms and the same indicators of fecal microbiome diversity, including the significant non-genetic factors as covariates. No genome-wide significant associations were identified after correction for multiple testing. A small fraction of previously reported associations between human genetic variants and specific taxa could be replicated in our cohort, while no replication was observed for any of the diversity metrics. ConclusionIn a well-characterized cohort of healthy individuals, we identified several non-genetic variables associated with fecal microbiome diversity. In contrast, host genetics only had a negligible influence. Demographic and environmental factors are thus the main contributors to fecal microbiome composition in healthy individuals.

genomics↗

bioRxiv2018

Genetic factors and age are the strongest predictors of humoral immune responses to common pathogens and vaccines

IntroductionHumoral immune responses to infectious agents or vaccination vary substantially among individuals, and many of the factors responsible for this variability remain to be defined. Current evidence suggests that human genetic variation influences (i) serum immunoglobulin levels, (ii) seroconversion rates, and (iii) intensity of antigen-specific immune responses. Here, we evaluate the impact of intrinsic (age and sex), environmental and genetic factors on the variability of humoral response to common pathogens and vaccines.\n\nMethodsWe characterized the serological response to 15 antigens from common human pathogens or vaccines, in an age- and sex-stratified cohort of 1,000 healthy individuals (Milieu Interieur cohort). Using clinical-grade serological assays, we measured total IgA, IgE, IgG and IgM levels, as well as qualitative (serostatus) and quantitative IgG responses to cytomegalovirus, Epstein-Barr virus, herpes simplex virus 1 & 2, varicella zoster virus, Helicobacter pylori, Toxoplasma gondii, influenza A virus, measles, mumps, rubella, and hepatitis B virus. Following genome-wide genotyping of single nucleotide polymorphisms and imputation, we examined associations between ~5 million genetic variants and antibody responses using single marker and gene burden tests.\n\nResults and discussionWe identified age and sex as important determinants of humoral response, with older individuals and women having higher rates of seropositivity for most antigens. Genome-wide association studies revealed significant associations between variants in the human leucocyte antigen (HLA) class II region on chromosome 6 and anti-EBV and anti-rubella IgG levels. We used HLA imputation to fine map these associations to amino acid variants in the peptide-binding groove of HLA-DR{beta}1 and HLA-DP{beta}1, respectively. We also observed significant associations for total IgA levels with two loci on chromosome 2 and with specific KIR-HLA combinations.\n\nConclusionsUsing extensive serological testing and genome-wide association analyses in a well-characterized cohort of healthy individuals, we demonstrate that age, sex and specific human genetic variants contribute to inter-individual variability in humoral response. By highlighting genes and pathways implicated in the normal antibody response to frequently encountered antigens, these findings provide a basis to better understand disease pathogenesis.

genomics↗