Immunological heterogeneity informs estimation of the durability of COVID-19 vaccine protection

Deciphering the properties of vaccines against coronavirus disease 2019 (COVID-19) is essential to predict the future course of the pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, current uncertainties about COVID-19 vaccine immunity raise the question of how much time will be needed to estimate these properties, in particular the durability of vaccine protection. Here we designed a simulation study, based on empirically validated epidemiological models of SARS-CoV-2 transmission, to predict the impact of a breadth of vaccines with different mean duration (range: 2–5 years) and heterogeneity (coefficient of variation range: 50–100%) of protection against infection. We then assessed how confidently the duration of protection could be estimated under a range of epidemiological scenarios in the year following the start of mass immunization. We found that lower population mean and higher inter-individual variability facilitated estimation of the duration of vaccine protection. Across the vaccines tested, high waning and high heterogeneity permitted complete identification of the duration of protection; in contrast, low waning and low heterogeneity allowed only estimation of the fraction of vaccinees with rapid loss of immunity. These findings suggest that key aspects of COVID-19 vaccine immunity can be estimated with limited epidemiological data. More generally, they highlight that immunological heterogeneity can sensitively determine the impact of COVID-19 vaccines and, it is likely, of other vaccines.

AB0444 СLINICAL-IMMUNOLOGICAL CHARACTERISTICS OF PATIENTS WITH INFLAMMATORY MYOPATHIES

Background:Inflammatory disorders of the skeletal muscle include polymyositis (PM), dermatomyositis (DM), amyopathic dermatomyositis ADM, (immune mediated) necrotizing myopathy (NM), overlap syndrome with myositis (overlap myositis, OM) and including anti-synthetase syndrome (ASS).The detection of myositis-specific antibodies, the clinical effect of which remains to be determined, may be of great importance for diagnosis.Objectives:To study clinical-immunological characteristics of patients with inflammatory myopathies.Methods:57 pts were enrolled in this study: 28 (47%) pts were diagnosed with DM, 14 (23%) pts – OM, 5(8%) pts – PM, 5 (8%) pts-NM, 4 (7%) pts-ADM, 1 (2%)- ACC. Duration of disease in average 11,29 (2-48) month. Standard clinical examination and laboratory immunological evaluation including myositis-specific autoantibodies were performed.Results:There were 3 age groups: 18-39 years old – 16 (28%) pts, 40-49 yo – 28 (49%) pts and > 60 yo – 13 (33%) pts. Symptoms of myositis were muscle weakness 57 (100%) pts, dysphagia 29 (51%) pts, arthritis -12 (21%) pts, Raynaud’s phenomenon 21 (37%) pts, skin lesions- 37 (65%) pts (Gottron signs- 7 (12%) pts, digital ulcers -11 (19) pts, panniculitis – 6(11%) pts, hand of mechanic 16(28%) pts). MMT 8 was 55,57 (SD 18,49) (20-80) score. Clinical features of myositis were myocarditis 8 (14%) pts and arrhythmia 9 (16%) pts, interstitial lung disease 20 (35%) pts, esophageal involvement 29 (51%) pts of them 5 (9%) pts needed enteral feeding. 2 (4%) pts had oncopathology. СК was increased in 49 (86%) pts: < 10 N -15 (26%) pts, >10 N – 28 (49%) pts, > 50 N – 6 (11%). ANA positive - in 39 (70%) pts. Antibodies identified in 25(44%) pts: Pm-Scl 7 (12%) pts, PL-7 1 (2%), Mi-2 10 (17,5%), Ku 2 (3,5%) pts, AMA-M2 2 (2%)pts, a-SRP 4 (7%) and SS-A/Ro-52 13 (23%), SS-A/Ro-60 2 (3%) pts.Conclusion:The group of inflammatory myopathies is characterized by clinical and immunological heterogeneity. Finding antibodies specific for myositis can help diagnose the disease.Disclosure of Interests:None declared.

Single-Cell Profiling to Explore Immunological Heterogeneity of Tumor Microenvironment in Breast Cancer

Immune infiltrates in the tumor microenvironment (TME) of breast cancer (BRCA) have been shown to play a critical role in tumorigenesis, progression, invasion, and therapy resistance, and thereby will affect the clinical outcomes of BRCA patients. However, a wide range of intratumoral heterogeneity shaped by the tumor cells and immune cells in the surrounding microenvironment is a major obstacle in understanding and treating BRCA. Recent progress in single-cell technologies such as single-cell RNA sequencing (scRNA-seq), mass cytometry, and digital spatial profiling has enabled the detailed characterization of intratumoral immune cells and vastly improved our understanding of less-defined cell subsets in the tumor immune environment. By measuring transcriptomes or proteomics at the single-cell level, it provides an unprecedented view of the cellular architecture consist of phenotypical and functional diversities of tumor-infiltrating immune cells. In this review, we focus on landmark studies of single-cell profiling of immunological heterogeneity in the TME, and discuss its clinical applications, translational outlook, and limitations in breast cancer studies.

TBIO-02. IMMUNE PROFILING OF RARE EMBRYONAL BRAIN TUMORS REVEAL EVIDENCE OF DYSREGULATED INTERFERON SIGNALLING AS A POTENTIAL DETERMINANT OF IMMUNOLOGICAL HETEROGENEITY

Embryonal brain tumors (EBTs) remain the most common malignant pediatric brain tumors. Despite recent advances and improved understanding of the molecular biology of EBTs, clinical outcomes remain poor for rare EBTs. Previous large-scale genomic studies of rare EBTs have shed light on distinct genomic, transcriptomic and epigenomic profiles. Interestingly, these studies have revealed prominent tumor heterogeneity that provides opportunity to develop novel treatment strategies to improve patient outcomes. To examine the tumor microenvironment and identify tumor- specific biological dependencies, we performed deconvolution analysis of bulk gene expression (171 RNA-seq, 236 microarrays) and 586 methylation arrays, which revealed significant intra and inter-tumoral heterogeneity and implicated interferon (IFN)-mediated signalling as a determinant of a distinct immunological profile in rare EBTs. To further elucidate the importance of IFN signalling, we performed scRNA-seq on 20 primary samples, which provided evidence of a spectrum of IFN-immunological responses that vary from immunosuppressive to immunologically exhaustive that occur in a host dependent manner. To further validate our findings, we utilised a genetically engineered murine model of Atypical Teratoid Rhabdoid Tumor and primary xenografts in humanised mice to corroborate our in-silico profiles in vivo. Through amalgamation of our in-silico data with our in vivo data, we have identified evidence that dysregulated IFN responses represent a core element of the immunological heterogeneity present within subsets of rare EBTs. An improved understanding of the immune milieu in rare EBTs will provide avenues to develop specific onco-immune targets to address this clinical need.

Immunological Heterogeneity

Ease of access to circulating peripheral blood cells (PBMCs) can offer unique insights into human immune function, as well as responses to vaccination and infection. Nevertheless, PBMC heterogeneity has been under-appreciated since results obtained from mixed populations may reflect changes in subset abundance as opposed to true age-related changes involving a specific subset. Technological advances have allowed for the examination of age-related heterogeneity with regards to systemic cytokine levels, immune cell frequencies and chemokine receptor expression by peripheral lymphocytes. Furthermore, introduction of sex as a variable in the examination of human PBMCs adds additional dimorphism to the study of aging and immunity including differences in epigenetic modifications, levels of pro-inflammatory activity and adaptive immunity.

Impact of Tumor and Immunological Heterogeneity on the Anti-Cancer Immune Response

Metastatic tumors are the primary cause of cancer-related mortality. In recent years, interest in the immunologic control of malignancy has helped establish escape from immunosurveillance as a critical requirement for incipient metastases. Our improved understanding of the immune system’s interactions with cancer cells has led to major therapeutic advances but has also unraveled a previously unsuspected level of complexity. This review will discuss the vast spatial and functional heterogeneity in the tumor-infiltrating immune system, with particular focus on natural killer (NK) cells, as well as the impact of tumor cell-specific factors, such as secretome composition, receptor–ligand repertoire, and neoantigen diversity, which can further drive immunological heterogeneity. We emphasize how tumor and immunological heterogeneity may undermine the efficacy of T-cell directed immunotherapies and explore the potential of NK cells to be harnessed to circumvent these limitations.