scholarly journals TAMI-01. NEOADJUVANT PD-1 ANTIBODY BLOCKADE REMODELS THE IMMUNE MICROENVIRONMENT OF METASTATIC BRAIN TUMORS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii212-ii213
Author(s):  
Lu Sun ◽  
Jenny Kienzler ◽  
Alexander Lee ◽  
Frances Chow ◽  
Carolina Chavez ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Single Cell ◽  
Immune Cell ◽  
Cytotoxic T Cells ◽  
Lymphoid Cells ◽  
New Combination ◽  
Inflammatory Microenvironment ◽  
Hla Dr ◽  
Line Standard

Abstract Brain metastases (BM) commonly arise in patients with melanoma, lung, and breast cancer. Currently, there are limited options for GBM and BM patients who have failed the first-line standard treatment, underscoring the importance of developing new therapeutic strategies. Last year, we and other groups evaluated the neoadjuvant timing of anti-PD-1 checkpoint blockade therapy in recurrent GBM (rGBM) patients, which resulted in a modest survival benefit. In light of the known effectiveness of anti-PD-1 as a systemic therapy to control melanoma and non-small cell lung cancer BM, we set out to study the anti-tumor immune response of BM patients to anti-PD-1 in the neoadjuvant setting. We posited that neoadjuvant anti-PD-1 in patients with BM would result in a stronger antitumoral immune response, which could be quantified at the single cell level. To test this, we made use of contemporary single cell techniques, including multiplex immunofluorescence, time-of-flight mass cytometry (CyTOF) and single-cell RNA sequencing (scRNAseq), to characterize the intratumoral immune cell populations and their transcriptomic profiles. We found that neoadjuvant anti-PD-1 significantly increased the number of tumor infiltrating T lymphocytes in BM compared to rGBM (2.5 fold in BM, p= 0.02 vs. 1.4 fold in rGBM, p= 0.19). Multiplex immunofluorescence analysis of T cells in BM samples revealed a change from T cell exclusion to a diffusely infiltrating phenotype after anti-PD-1 treatment. Importantly, BM showed a higher fraction of effector/cytotoxic T cells compared to rGBM (7.3% vs. 0.9% of lymphoid cells, p= 0.005) and anti-PD-1 further enhanced this population. In the myeloid compartment of BM, neoadjuvant anti-PD-1 increased the frequency of HLA-DR+CD206- M1-like macrophages, implicating a pro-inflammatory microenvironment. In summary, our study delineated the immune cell subtypes altered by neoadjuvant anti-PD-1 and offers insights into new combination therapies that can help understand the clinical efficacy of immunotherapy for BM and GBM patients.

scholarly journals High-dimensional cytometric analysis of colorectal cancer reveals novel mediators of antitumour immunity

Gut ◽  
2019 ◽  
Vol 69 (4) ◽  
pp. 691-703 ◽  
Author(s):  
Natasja L de Vries ◽  
Vincent van Unen ◽  
Marieke E Ijsselsteijn ◽  
Tamim Abdelaal ◽  
Ruud van der Breggen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Lymph Nodes ◽  
Single Cell ◽  
Immune Cell ◽  
Γδ T Cells ◽  
High Dimensional ◽  
Hla Dr ◽  
Healthy Mucosa ◽  
Immune Contexture

ObjectiveA comprehensive understanding of anticancer immune responses is paramount for the optimal application and development of cancer immunotherapies. We unravelled local and systemic immune profiles in patients with colorectal cancer (CRC) by high-dimensional analysis to provide an unbiased characterisation of the immune contexture of CRC.DesignThirty-six immune cell markers were simultaneously assessed at the single-cell level by mass cytometry in 35 CRC tissues, 26 tumour-associated lymph nodes, 17 colorectal healthy mucosa and 19 peripheral blood samples from 31 patients with CRC. Additionally, functional, transcriptional and spatial analyses of tumour-infiltrating lymphocytes were performed by flow cytometry, single-cell RNA-sequencing and multispectral immunofluorescence.ResultsWe discovered that a previously unappreciated innate lymphocyte population (Lin–CD7+CD127–CD56+CD45RO+) was enriched in CRC tissues and displayed cytotoxic activity. This subset demonstrated a tissue-resident (CD103+CD69+) phenotype and was most abundant in immunogenic mismatch repair (MMR)-deficient CRCs. Their presence in tumours was correlated with the infiltration of tumour-resident cytotoxic, helper and γδ T cells with highly similar activated (HLA-DR+CD38+PD-1+) phenotypes. Remarkably, activated γδ T cells were almost exclusively found in MMR-deficient cancers. Non-activated counterparts of tumour-resident cytotoxic and γδ T cells were present in CRC and healthy mucosa tissues, but not in lymph nodes, with the exception of tumour-positive lymph nodes.ConclusionThis work provides a blueprint for the understanding of the heterogeneous and intricate immune landscape of CRC, including the identification of previously unappreciated immune cell subsets. The concomitant presence of tumour-resident innate and adaptive immune cell populations suggests a multitargeted exploitation of their antitumour properties in a therapeutic setting.

scholarly journals Single-Cell RNA Sequencing of Peripheral Blood Reveals Immune Cell Signatures in Alzheimer’s Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Hui Xu ◽  
Jianping Jia
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Single Cell ◽  
Immune Cells ◽  
Peripheral Blood ◽  
Immune Cell ◽  
Adaptive Immune Response ◽  
Immune Repertoire ◽  
Adaptive Immune ◽  
Peripheral Immune Cells

The peripheral immune system is thought to affect the pathology of the central nervous system in Alzheimer’s disease (AD). However, current knowledge is inadequate for understanding the characteristics of peripheral immune cells in AD. This study aimed to explore the molecular basis of peripheral immune cells and the features of adaptive immune repertoire at a single cell level. We profiled 36,849 peripheral blood mononuclear cells from AD patients with amyloid-positive status and normal controls with amyloid-negative status by 5’ single-cell transcriptome and immune repertoire sequencing using the cell ranger standard analysis procedure. We revealed five immune cell subsets: CD4+ T cells, CD8+ T cells, B cells, natural killer cells, and monocytes–macrophages cells, and disentangled the characteristic alterations of cell subset proportion and gene expression patterns in AD. Thirty-one cell type-specific key genes, comprising abundant human leukocyte antigen genes, and multiple immune-related pathways were identified by protein–protein interaction network and pathway enrichment analysis. We also found high-frequency amplification clonotypes in T and B cells and decreased diversity in T cells in AD. As clone amplification suggested the activation of an adaptive immune response against specific antigens, we speculated that the peripheral adaptive immune response, especially mediated by T cells, may have a role in the pathogenesis of AD. This finding may also contribute to further research regarding disease mechanism and the development of immune-related biomarkers or therapy.

scholarly journals Hepatitis E Virus Infection—Immune Responses to an Underestimated Global Threat

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2281
Author(s):  
Paul Kupke ◽  
Jens M. Werner
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Disease Progression ◽  
Hepatitis E Virus ◽  
Cytotoxic T Cells ◽  
Pegylated Interferon ◽  
Hepatitis E ◽  
Lymphoid Cells ◽  
Clinical Samples ◽  
Global Threat

Infection with the hepatitis E virus (HEV) is one of the main ubiquitous causes for developing an acute hepatitis. Moreover, chronification plays a predominant role in immunocompromised patients such as transplant recipients with more frequent severe courses. Unfortunately, besides reduction of immunosuppression and off-label use of ribavirin or pegylated interferon alfa, there is currently no specific anti-viral treatment to prevent disease progression. So far, research on involved immune mechanisms induced by HEV is limited. It is very difficult to collect clinical samples especially from the early phase of infection since this is often asymptomatic. Nevertheless, it is certain that the outcome of HEV-infected patients correlates with the strength of the proceeding immune response. Several lymphoid cells have been identified in contributing either to disease progression or achieving sustained virologic response. In particular, a sufficient immune control by both CD4+ and CD8+ T cells is necessary to prevent chronic viral replication. Especially the mechanisms underlying fulminant courses are poorly understood. However, liver biopsies indicate the involvement of cytotoxic T cells in liver damage. In this review, we aimed to highlight different parts of the lymphoid immune response against HEV and point out questions that remain unanswered regarding this underestimated global threat.

Local immune response in colon cancer: Indicative of good or poor prognosis?

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 213-213
Author(s):  
Peter G Alexander ◽  
Jitwadee AF In ◽  
Antonia K. Roseweir ◽  
Arfon GMT Powell ◽  
Joanne Edwards ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Inflammatory Infiltrate ◽  
Immune Cell ◽  
Cytotoxic T Cells ◽  
Cancer Specific Survival ◽  
Good Outcome ◽  
Poor Outcome

213 Background: The tumour microenvironment is an important determinant of survival in patients with colon cancer. Although the generalised inflammatory infiltrate as assessed by Klintrup-Mäkinen (KM) grade is a stage-independent prognostic marker, immunohistochemical staining for specific immune cell populations, such as T-cells, may have greater prognostic value. The present study examines the clinical utility of combined assessment of KM grade in addition to cytotoxic (CD8) and regulatory (FoxP3) T-cells. Methods: KM, CD8 and FoxP3 were assessed retrospectively in a cohort of 520 patients with stage I-III colon cancers. The relationship between KM grade, T-cell density and cancer-specific survival was examined. Results: KM was high in 33% of patients, of which: 16% had high FoxP3, 12% high CD8 and 56% both FoxP3 and CD8, while the remaining 15% were high KM alone. Conversely, 67% had low KM and of these: 47% had high CD8 alone or with FoxP3; 27% were high for FoxP3 alone and 25% had no inflammatory infiltrate. KM in the presence of other T-cells resulted in good outcome (Table), whereas CD8 with low KM with or without FoxP3 resulted in intermediate outcome. FoxP3 alone with low KM resulted in poor outcome. Similarly, KM alone without T-cells resulted in poor outcome. When no inflammatory cells were present, outcomes were comparable to KM or FoxP3 alone. Conclusions: A co-ordinated immune response results in good outcome and this can be assessed using a combination of a simple H&E based method (KM) in addition to T-cell markers. Where KM is low, despite the presence of cytotoxic T-cells, survival outcome is worse. Conversely, high KM in the absence of T-cells, or FoxP3 alone, are associated with poor outcome, comparable to no inflammatory response. [Table: see text]

747 Evaluation of immune microenvironment of primary lung cancer and synchronous liver metastasis with multispectral imaging system

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A795-A795
Author(s):  
Hyeonbin Cho ◽  
Jae-Hwan Kim ◽  
Ji-Hyun Kim
Keyword(s):  
T Cells ◽  
Liver Metastasis ◽  
Multispectral Imaging ◽  
Immune Cell ◽  
Imaging System ◽  
Cytotoxic T Cells ◽  
Primary Lung Cancer ◽  
Helper T Cells ◽  
Synchronous Liver Metastasis ◽  
Immune Microenvironment

BackgroundCancer immunotherapy (CIT) has substantially improved the survival of cancer patients. However, according to recent studies, liver metastasis was reported to predict worse outcomes for CIT. The main objective of the study is to evaluate the differences in the immune microenvironment (IME) between the primary lung cancer (PL) and synchronous liver metastasis (LM) using a multispectral imaging system.MethodsSix immune markers (CD4, CD8, CTLA-4, granzyme B (GZB), Foxp3 and PD-L1) were analyzed using a multiplex IHC system and inForm program (Akoya) on paired lung-liver samples of 10 patients. Cells were categorized into tumor nest and stroma, and cell counts per unit area were measured for comparison.ResultsThe number of tumor-infiltrating cytotoxic T cells (TIL) in PL (262.5 cells/mm2) was higher than that of LM (113.3 cells/mm2). Additionally, the ratio between the number of TIL and non-TIL was greater in PL (0.31) compared to that of LM (0.26). A similar trend appeared for Helper T cells and regulatory T cells (Treg), as PL consisted of higher numbers of T cells (791.8 Helper T cells/mm2, 195.7 Treg/mm2) than LM (626.3 Helper T cells/mm2, 121.3 Treg/mm2). However, cytotoxic T cells exhibiting GZB+ and CTLA-4- were fewer in PL (140.2 cells/mm2) than in LM (203.3 cells/mm2), and the ratio is 0.69. The mean number of GZB+ TIL in PL (32.5 cells/mm2) was lower than in LM (35.3 cells/mm2), and their proportions among total TIL counts were 0.12 and 0.31, respectively. In PL, GZB+: GZB- ratio is 0.16 while the ratio is 1.91 for LM. A fewer number of TILs exhibiting GZB suggests that PL has lower efficiency in immune response than LM. Another crucial checkpoint receptor that inhibits immune response, CTLA-4, was more prevalent in PL, with CTLA-4+: CTLA-4- ratio in Treg being 0.36 in PL, compared to 0.11 in LM. The tumor proportion score (TPS) of PD-L1 was higher in PL than LM (40.0 vs. 6.6).ConclusionsIn our study, we showed the differences in the numbers of TIL or regulatory T cells and expressions of immune checkpoint receptors (PD-L1, CTLA-4), which significantly influence outcomes for CIT. The study is ongoing to confirm different IME between the PL and LM groups in a larger tumor cohort.ReferencesPeng, Jianhong, et al., Immune Cell Infiltration in the Microenvironment of Liver Oligometastasis from Colorectal Cancer: Intratumoural CD8/CD3 Ratio Is a Valuable Prognostic Index for Patients Undergoing Liver Metastasectomy. Cancers 2019 Dec; 11(12): 1922. https://doi.org/10.3390/cancers11121922Tumeh, Paul C., et al., Liver Metastasis and treatment outcome with Anti-PD-1 monoclonal antibody in patients with melanoma and NSCLC. Cancer Immunol Res 2017 May; 5(5): 417–424. doi: 10.1158/2326-6066.CIR-16-0325Parra, E.R., Immune Cell Profiling in Cancer Using Multiplex Immunofluorescence and Digital Analysis Approaches; Streckfus, C.F., Ed.; IntechOpen: London, UK, 2018; pp. 1–13. doi: 10.5772/intechopen.80380Ribas, A., Hu-Lieskovan, S., What does PD-L1 positive or negative mean?. The Journal of Experimental Medicine 2016;213(13):2835–2840. https://doi.org/10.1084/jem.20161462

scholarly journals AB0128 CXCL5 DAMPENS INFLAMMATION IN THE PRE-CLINICAL MODEL OF SYSTEMIC LUPUS ERYTHEMATOSUS VIA THE ORCHESTRAL EFFECT OF REGULATING NEUTROPHIL TRAFFICKING AND SUPPRESSING HELPER T CELL-MEDIATED IMMUNE RESPONSE

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1365.2-1365
Author(s):  
X. Fan ◽  
D. Guo ◽  
C. T. Ng ◽  
A. Law ◽  
Z. Y. Poon ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Lupus Erythematosus ◽  
Immune Cell ◽  
Systemic Lupus ◽  
Helper T Cell ◽  
Clinical Model ◽  
Cell Mediated Immune Response

Background:Patients with systemic lupus erythematosus (SLE) suffer from severe morbidity and mortality1-4, either from the disease itself or from side effects of immunosuppression5. Discovery of novel effective therapies with less toxicity is an urgent need.Objectives:The aim of this study is to elucidate the therapeutic potential and working mechanism of cytokine CXCL5 in lupus mice.Methods:Treatment with CXCL5, bone marrow (BM)-MSCs, standard of care (SOC) with combination of methylprednisolone and cyclophosphamide was given to 16-week-old Faslprmice. Mice were monitored for 10 weeks. Splenic immune cell subsets were measured by flow cytometry. Circulating cytokine and immunoglobulin were detected by Luminex technology. Renal function was evaluated by urinary spot albumin creatinine ratio. In situ renal immune cell infiltration and complement 3 deposition were detected by Haematoxylin and Eosin (H&E) staining and immunohistochemistry.Results:CXCL5 demonstrated consistent and potent immunosuppressive capacity in suppressing SLE with reduced autoantibody secretion, lymphoproliferation and preserved kidney function. With further exploration, we proved that CXCL5 reduced the proliferation of helper T cells (TH1 and TH2) in thein vitrofunctional assay. When we administrated CXCL5 to lupus mice, it promoted the proliferation of regulatory T cells and reduced the proliferation of TH17 cells, macrophages and neutrophils. Multiple proinflammatory cytokines including IL-2, IL-6, IL-12, IL-17A, KC/CXCL1, MIP-1β/CCL4 and TNF-α were also reduced. When combined with SOC, CXCL5 boosted its therapeutic effect and reduced the relevant indices of disease activity. When we correlated the effect of four different treatment groups (CXCL5, BM-MSCs, SOC, and CXCL5 plus SOC) on mice survival and target cell changes, we found that TH17 cells were the key effector cells involved in the pathogenesis of SLE.Conclusion:These findings demonstrated that CXCL5 dampens inflammation in the pre-clinical model of systemic lupus erythematosus via the orchestral effect of regulating neutrophil trafficking and suppressing helper T cell-mediated immune response. Administrating exogenous CXCL5 might be an attractive option to treat patients with lupus.References:[1]Ji S, Guo Q, Han Y, Tan G, Luo Y, Zeng F. Mesenchymal stem cell transplantation inhibits abnormal activation of Akt/GSK3beta signaling pathway in T cells from systemic lupus erythematosus mice.Cell Physiol Biochem.2012;29(5-6):705-712.[2]Peng SL. Altered T and B lymphocyte signaling pathways in lupus.Autoimmun Rev.2009;8(3):179-183.[3]Ferucci ED, Johnston JM, Gaddy JR, et al. Prevalence and incidence of systemic lupus erythematosus in a population-based registry of American Indian and Alaska Native people, 2007-2009.Arthritis Rheumatol.2014;66(9):2494-2502.[4]Jakes RW, Bae SC, Louthrenoo W, Mok CC, Navarra SV, Kwon N. Systematic review of the epidemiology of systemic lupus erythematosus in the Asia-Pacific region: prevalence, incidence, clinical features, and mortality.Arthritis Care Res (Hoboken).2012;64(2):159-168.[5]Sattwika PD, Mustafa R, Paramaiswari A, Herningtyas EH. Stem cells for lupus nephritis: a concise review of current knowledge.Lupus.2018;27(12):1881-1897.Acknowledgments:The work was supported by SMART II Centre Grant (NMRC/CG/M011/2017_SGH) and SingHealth Foundation (SHF/FG638P/2016).Disclosure of Interests:None declared

scholarly journals Heterologous vaccination regimens with self-amplifying RNA and adenoviral COVID vaccines induce robust immune responses in mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Alexandra J. Spencer ◽  
Paul F. McKay ◽  
Sandra Belij-Rammerstorfer ◽  
Marta Ulaszewska ◽  
Cameron D. Bissett ◽  
...  
Keyword(s):  
Immune Response ◽  
Clinical Trials ◽  
T Cells ◽  
Immune Responses ◽  
Viral Vectors ◽  
Cytotoxic T Cells ◽  
Antibody Responses ◽  
Limited Data ◽  
Vectored Vaccine ◽  
Cellular Immune

AbstractSeveral vaccines have demonstrated efficacy against SARS-CoV-2 mediated disease, yet there is limited data on the immune response induced by heterologous vaccination regimens using alternate vaccine modalities. Here, we present a detailed description of the immune response, in mice, following vaccination with a self-amplifying RNA (saRNA) vaccine and an adenoviral vectored vaccine (ChAdOx1 nCoV-19/AZD1222) against SARS-CoV-2. We demonstrate that antibody responses are higher in two-dose heterologous vaccination regimens than single-dose regimens. Neutralising titres after heterologous prime-boost were at least comparable or higher than the titres measured after homologous prime boost vaccination with viral vectors. Importantly, the cellular immune response after a heterologous regimen is dominated by cytotoxic T cells and Th1+ CD4 T cells, which is superior to the response induced in homologous vaccination regimens in mice. These results underpin the need for clinical trials to investigate the immunogenicity of heterologous regimens with alternate vaccine technologies.

scholarly journals TAMI-07. THE IMMUNE MICROENVIRONMENT IN LOWER GRADE GLIOMAS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii214-ii214
Author(s):  
Anupam Kumar ◽  
Katharine Chen ◽  
Claudia Petritsch ◽  
Theodore Nicolaides ◽  
Mariarita Santi-Vicini ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Cd8 T Cells ◽  
Molecular Mechanisms ◽  
T Regulatory Cells ◽  
Immune Cell ◽  
T Cell Response ◽  
Cytotoxic T Cell ◽  
Lower Grade ◽  
Functional Relationships

Abstract The determinants of the tumor-associated immune response in brain tumors are poorly understood. Using tumor samples from two molecularly distinct subtypes of lower grade glioma, MAPK-driven glioma with biallelic inactivation of CDKN2A (n=30) and IDH-mutant, 1p/19q-intact astrocytoma (n=29), we demonstrate qualitative and quantitative differences in the tumor-associated immune response and we investigate the molecular mechanisms involved. Histologically the MAPK-driven gliomas were comprised of pleomorphic xanthoastrocytoma (PXA) (n=11) and anaplastic PXA (n=19). Seven patients had paired samples from two sequential surgeries. Immune cell populations and their activity were determined by quantitative multiplex immunostaining and Digital Spatial Profiling and gene expression was analyzed by Nanostring. Functional studies were performed using established cell lines and two new patient-derived lines from MAPK-driven LGGs. MAPK-driven tumors exhibited an increased number of CD8+ T cells and tumor-associated microglial/macrophage (TAMs), including CD163+ TAMs, as compared to IDH-mutant astrocytoma. In contrast, IDH-mutant tumors had increased FOXP3+ immunosuppressive T regulatory cells. Transcriptional and protein level analyses in MAPK-driven tumors suggested an active cytotoxic T cell response with robust expression of granzyme B, present on 27% of CD8+ T cells, increased MHC class I expression, and altered cytokine profiles. Interestingly, MAPK-driven tumors also had increased expression of immunosuppressive molecules, including CXCR4, PD-L1, and VEGFA. Expression differences for cell surface and secreted proteins were confirmed in patient-derived tumor lines and functional relationships between altered chemokine expression and immune cell infiltration was investigated. Our data provide novel insights into the immune contexture of MAPK driven LGGs and suggest MAPK driven gliomas with biallelic inactivation of CDKN2A may be particularly vulnerable to immunotherapeutic modulation

scholarly journals Single-cell multi-omics analysis of the immune response in COVID-19

2021 ◽  
Author(s):  
Emily Stephenson ◽  
◽  
Gary Reynolds ◽  
Rachel A. Botting ◽  
Fernando J. Calero-Nieto ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Single Cell ◽  
Mononuclear Cells ◽  
Severe Disease ◽  
Effector Memory ◽  
Peripheral Blood Mononuclear ◽  
Cross Sectional ◽  
Hematopoietic Stem ◽  
Symptomatic Disease

AbstractAnalysis of human blood immune cells provides insights into the coordinated response to viral infections such as severe acute respiratory syndrome coronavirus 2, which causes coronavirus disease 2019 (COVID-19). We performed single-cell transcriptome, surface proteome and T and B lymphocyte antigen receptor analyses of over 780,000 peripheral blood mononuclear cells from a cross-sectional cohort of 130 patients with varying severities of COVID-19. We identified expansion of nonclassical monocytes expressing complement transcripts (CD16+C1QA/B/C+) that sequester platelets and were predicted to replenish the alveolar macrophage pool in COVID-19. Early, uncommitted CD34+ hematopoietic stem/progenitor cells were primed toward megakaryopoiesis, accompanied by expanded megakaryocyte-committed progenitors and increased platelet activation. Clonally expanded CD8+ T cells and an increased ratio of CD8+ effector T cells to effector memory T cells characterized severe disease, while circulating follicular helper T cells accompanied mild disease. We observed a relative loss of IgA2 in symptomatic disease despite an overall expansion of plasmablasts and plasma cells. Our study highlights the coordinated immune response that contributes to COVID-19 pathogenesis and reveals discrete cellular components that can be targeted for therapy.

scholarly journals Distribution of tumor-infiltrating-T-lymphocytes and possible tumor-escape mechanisms avoiding immune cell attack in locally advanced adenocarcinomas of the esophagus

2021 ◽  
Author(s):  
M. Schoemmel ◽  
◽  
H. Loeser ◽  
M. Kraemer ◽  
S. Wagener-Ryczek ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Cell ◽  
Locally Advanced ◽  
Tumor Escape ◽  
Inflammatory Microenvironment ◽  
Advanced Tumor ◽  
Tumor Stages ◽  
Tumor Center ◽  
Class 1

Abstract Introduction The inflammatory microenvironment has emerged as one of the focuses of cancer research. Little is known about the immune environment in esophageal adenocarcinoma (EAC) and possible tumor-escape mechanisms to avoid immune cell attack. Patients and methods We measured T cell inflammation (CD3, CD8) in the microenvironment using a standardized software-based evaluation algorithm considering different predefined tumor areas as well as expression of MHC class 1 and PD-L1 on 75 analyzable primarily resected and locally advanced (≥ pT2) EACs. We correlated these findings statistically with clinical data. Results Patients with high amounts of T cell infiltration in their tumor center showed a significant survival benefit of 41.4 months compared to 16.3 months in T cell poor tumors (p = 0.025), although CD3 fails to serve as an independent prognostic marker in multivariate analysis. For the invasion zone, a correlation between number of T-cells and overall survival was not detectable. Loss of MHC1 protein expression on tumor cells was seen in 32% and PD-L1 expression using the combined positive score (CPS) in 21.2%. Most likely due to small numbers of cases, both markers are not prognostically relevant, even though PD-L1 expression correlates with advanced tumor stages. Discussion Our analyses reveal an outstanding, though not statistically independent, prognostic relevance of T-cell-rich inflammation in our group of EACs, in particular driven by the tumor center. For the first time, we describe that the inner part of the invasion zone in EACs shows significantly fewer T-cells than other tumor segments and is prognostically irrelevant. We also demonstrate that the loss of antigen presenting ability via MHC1 downregulation by the carcinoma cells is a common escape mechanism in EACs. Future work will need to show whether tumors with MHC class 1 loss respond less well to immunotherapy.

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