scholarly journals Resolving the Paradox of Colon Cancer Through the Integration of Genetics, Immunology, and the Microbiota

2020 ◽  
Vol 11 ◽  
Author(s):  
Marine Fidelle ◽  
Satoru Yonekura ◽  
Marion Picard ◽  
Alexandria Cogdill ◽  
Antoine Hollebecque ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Effector Memory ◽  
Mesenteric Lymph Nodes ◽  
Normal Epithelium ◽  
Cell Responses ◽  
Cellular Immune Responses ◽  
Mesenteric Lymph ◽  
Specific Memory ◽  
Cellular Immune

While colorectal cancers (CRC) are paradigmatic tumors invaded by effector memory lymphocytes, the mechanisms accounting for the relative resistance of MSI negative CRC to immunogenic cell death mediated by oxaliplatin and immune checkpoint inhibitors has remained an open conundrum. Here, we propose the viewpoint where its microenvironmental contexture could be explained -at least in part- by macroenvironmental cues constituted by the complex interplay between the epithelial barrier, its microbial ecosystem, and the local immune system. Taken together this dynamic ménage-à-trois offers novel coordinated actors of the humoral and cellular immune responses actionable to restore sensitivity to immune checkpoint inhibition. Solving this paradox involves breaking tolerance to crypt stem cells by inducing the immunogenic apoptosis of ileal cells in the context of an ileal microbiome shifted towards immunogenic bacteria using cytotoxicants. This manoeuver results in the elicitation of a productive Tfh and B cell dialogue in mesenteric lymph nodes culminating in tumor-specific memory CD8+ T cell responses sparing the normal epithelium.

scholarly journals Virus-specific memory T cell responses unmasked by immune checkpoint blockade cause hepatitis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
James A. Hutchinson ◽  
Katharina Kronenberg ◽  
Paloma Riquelme ◽  
Jürgen J. Wenzel ◽  
Gunther Glehr ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Serum Antibody ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Effector Memory ◽  
Specific Memory ◽  
Immune Mediated ◽  
Antibody Titres ◽  
Pre Treatment ◽  
After Cancer

AbstractTreatment of advanced melanoma with combined PD-1/CTLA-4 blockade commonly causes serious immune-mediated complications. Here, we identify a subset of patients predisposed to immune checkpoint blockade-related hepatitis who are distinguished by chronic expansion of effector memory CD4+ T cells (TEM cells). Pre-therapy CD4+ TEM cell expansion occurs primarily during autumn or winter in patients with metastatic disease and high cytomegalovirus (CMV)-specific serum antibody titres. These clinical features implicate metastasis-dependent, compartmentalised CMV reactivation as the cause of CD4+ TEM expansion. Pre-therapy CD4+ TEM expansion predicts hepatitis in CMV-seropositive patients, opening possibilities for avoidance or prevention. 3 of 4 patients with pre-treatment CD4+ TEM expansion who received αPD-1 monotherapy instead of αPD-1/αCTLA-4 therapy remained hepatitis-free. 4 of 4 patients with baseline CD4+ TEM expansion given prophylactic valganciclovir and αPD-1/αCTLA-4 therapy remained hepatitis-free. Our findings exemplify how pathogen exposure can shape clinical reactions after cancer therapy and how this insight leads to therapeutic innovations.

scholarly journals Comprehensive Epitope Analysis of Human Immunodeficiency Virus Type 1 (HIV-1)-Specific T-Cell Responses Directed against the Entire Expressed HIV-1 Genome Demonstrate Broadly Directed Responses, but No Correlation to Viral Load

2003 ◽  
Vol 77 (3) ◽  
pp. 2081-2092 ◽  
Author(s):  
M. M. Addo ◽  
X. G. Yu ◽  
A. Rathod ◽  
D. Cohen ◽  
R. L. Eldridge ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Responses ◽  
Protein Subunits ◽  
Cell Responses ◽  
Cellular Immune Responses ◽  
Immunodeficiency Virus ◽  
Total Magnitude ◽  
Cellular Immune ◽  
Hiv 1

ABSTRACT Cellular immune responses play a critical role in the control of human immunodeficiency virus type 1 (HIV-1); however, the breadth of these responses at the single-epitope level has not been comprehensively assessed. We therefore screened peripheral blood mononuclear cells (PBMC) from 57 individuals at different stages of HIV-1 infection for virus-specific T-cell responses using a matrix of 504 overlapping peptides spanning all expressed HIV-1 proteins in a gamma interferon-enzyme-linked immunospot (Elispot) assay. HIV-1-specific T-cell responses were detectable in all study subjects, with a median of 14 individual epitopic regions targeted per person (range, 2 to 42), and all 14 HIV-1 protein subunits were recognized. HIV-1 p24-Gag and Nef contained the highest epitope density and were also the most frequently recognized HIV-1 proteins. The total magnitude of the HIV-1-specific response ranged from 280 to 25,860 spot-forming cells (SFC)/106 PBMC (median, 4,245) among all study participants. However, the number of epitopic regions targeted, the protein subunits recognized, and the total magnitude of HIV-1-specific responses varied significantly among the tested individuals, with the strongest and broadest responses detectable in individuals with untreated chronic HIV-1 infection. Neither the breadth nor the magnitude of the total HIV-1-specific CD8+-T-cell responses correlated with plasma viral load. We conclude that a peptide matrix-based Elispot assay allows for rapid, sensitive, specific, and efficient assessment of cellular immune responses directed against the entire expressed HIV-1 genome. These data also suggest that the impact of T-cell responses on control of viral replication cannot be explained by the mere quantification of the magnitude and breadth of the CD8+-T-cell response, even if a comprehensive pan-genome screening approach is applied.

scholarly journals Lactobacillus reuteri DSM 17938 differentially modulates effector memory T cells and Foxp3+ regulatory T cells in a mouse model of necrotizing enterocolitis

2014 ◽  
Vol 307 (2) ◽  
pp. G177-G186 ◽  
Author(s):  
Yuying Liu ◽  
Dat Q. Tran ◽  
Nicole Y. Fatheree ◽  
J. Marc Rhoads
Keyword(s):  
T Cells ◽  
Lymph Nodes ◽  
Necrotizing Enterocolitis ◽  
Lactobacillus Reuteri ◽  
Intestinal Inflammation ◽  
Treg Cells ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Mesenteric Lymph Nodes ◽  
Mesenteric Lymph

Necrotizing enterocolitis (NEC) is an inflammatory disease with evidence of increased production of proinflammatory cytokines in the intestinal mucosa. Lactobacillus reuteri DSM 17938 (LR17938) has been shown to have anti-inflammatory activities in an experimental model of NEC. Activated effector lymphocyte recruitment to sites of inflammation requires the sequential engagement of adhesion molecules such as CD44. The phenotype of CD44+CD45RBlo separates T effector/memory (Tem) cells from naive (CD44−CD45RBhi) cells. It is unknown whether these Tem cells participate in the inflammation associated with NEC and can be altered by LR17938. NEC was induced in 8- to 10-day-old C57BL/6J mice by gavage feeding with formula and exposure to hypoxia and cold stress for 4 days. Survival curves and histological scores were analyzed. Lymphocytes isolated from mesenteric lymph nodes and ileum were labeled for CD4, CD44, CD45RB, intracellular Foxp3, and Helios and subsequently analyzed by flow cytometry. LR17938 decreased mortality and the incidence and severity of NEC. The percentage of Tem cells in the ileum and mesenteric lymph nodes was increased in NEC but decreased by LR17938. Conversely, the percentage of CD4+Foxp3+ regulatory T (Treg) cells in the intestine decreased during NEC and was restored to normal by LR17938. The majority of the Treg cells preserved by LR17938 were Helios+ subsets, possibly of thymic origin. In conclusion, LR17938 may represent a useful treatment to prevent NEC. The mechanism of protection by LR17938 involves modulation of the balance between Tem and Treg cells. These T cell subsets might be potential biomarkers and therapeutic targets during intestinal inflammation.

scholarly journals 540 Baseline mTOR transcriptional signatures in CD8 T cells are associated with immune-related adverse events but not anti-tumor responses in patients receiving immune checkpoint inhibitors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A570-A570
Author(s):  
Chen Zhao ◽  
Matthew Mule ◽  
Andrew Martins ◽  
Iago Pinal Fernandez ◽  
Renee Donahue ◽  
...  
Keyword(s):  
T Cells ◽  
Adverse Events ◽  
Tumor Immunity ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Effector Memory ◽  
Link Type ◽  
Anti Tumor Activity

BackgroundImmune checkpoint inhibitors (ICIs) have changed the cancer treatment landscape, but immune-related adverse events (irAEs) can affect a wide range of tissues in patients receiving ICIs. Severe irAEs can be life-threatening or fatal and prohibit patients from receiving further ICI treatment. While the clinical features of irAEs are well documented, the pathological mechanisms and predictive biomarkers are largely unknown. In addition, there is a critical need to preserve ICI-induced anti-tumor immunity while controlling for irAEs, which requires deciphering molecular and cellular signatures associated specifically with irAEs beyond those more generally linked to anti-tumor immunity.MethodsTo unbiasedly identify immune cells and states associated with irAEs, we applied CITE-seq to measure transcripts and surface proteins (83 protein markers) from PBMCs collected from patients with thymic epithelial tumors before and after treatment with an anti-PD-L1 antibody (avelumab, NCT01772004, NCT03076554).ResultsSamples from 9 patients were analyzed. No patient had a history of pre-existing paraneoplastic autoimmune disease. Anti-tumor activity was observed in all cases, and 5 patients had clinical and/or biochemical evidence of immune-related muscle inflammation (myositis with or without myocarditis). Multilevel models applied within highly resolved cell clusters revealed transcriptional states associated with ICI response and more uniquely with irAEs. A total of 190,000 cells were included in the analysis after quality control. Most notably, CD45RA+ effector memory CD8 T cells with an mTOR transcriptional signature were highly enriched at baseline and post treatment in patients with irAEs.ConclusionsOur findings suggest the potential therapeutic avenues by using mTOR inhibitors to dampen autoimmune responses while potentially sparing anti-tumor activity, to prevent treatment discontinuation and improve clinical outcomes for cancer patients treated with ICIs.AcknowledgementsThis research was supported in part by the Intramural Research Program of the NCI (the Center for Cancer Research), NIAID and NIAMS, and through a Cooperative Research and Development Agreement between the National Cancer Institute and EMD Serono.Trial RegistrationNCT01772004, NCT03076554Ethics ApprovalThis study is approved by NCI institutional review board.

scholarly journals Baseline Levels of Influenza-Specific B Cells and T Cell Responses Modulate Human Immune Responses to Swine Variant Influenza A/H3N2 Vaccine

Vaccines ◽  
2020 ◽  
Vol 8 (1) ◽  
pp. 126
Author(s):  
Lilin Lai ◽  
Nadine Rouphael ◽  
Yongxian Xu ◽  
Amy C. Sherman ◽  
Srilatha Edupuganti ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Influenza A ◽  
Vaccine Dose ◽  
T Cell Responses ◽  
Post Vaccination ◽  
Cell Responses ◽  
Cellular Immune Responses ◽  
Cellular Immune

The cellular immune responses elicited by an investigational vaccine against an emergent variant of influenza (H3N2v) are not fully understood. Twenty-five subjects, enrolled in an investigational influenza A/H3N2v vaccine study, who received two doses of vaccine 21 days apart, were included in a sub-study of cellular immune responses. H3N2v-specific plasmablasts were determined by ELISpot 8 days after each vaccine dose and H3N2v specific CD4+ T cells were quantified by intracellular cytokine and CD154 (CD40 ligand) staining before vaccination, 8 and 21 days after each vaccine dose. Results: 95% (19/20) and 96% (24/25) subjects had pre-existing H3N2v specific memory B, and T cell responses, respectively. Plasmablast responses at Day 8 after the first vaccine administration were detected against contemporary H3N2 strains and correlated with hemagglutination inhibition HAI (IgG: p = 0.018; IgA: p < 0.001) and Neut (IgG: p = 0.038; IgA: p = 0.021) titers and with memory B cell frequency at baseline (IgA: r = 0.76, p < 0.001; IgG: r = 0.74, p = 0.0001). The CD4+ T cells at Days 8 and 21 expanded after prime vaccination and this expansion correlated strongly with early post-vaccination HAI and Neut titers (p ≤ 0.002). In an adult population, the rapid serological response observed after initial H3N2v vaccination correlates with post-vaccination plasmablasts and CD4+ T cell responses.

scholarly journals Monitoring CD8 T cell responses to NY-ESO-1: Correlation of humoral and cellular immune responses

2000 ◽  
Vol 97 (9) ◽  
pp. 4760-4765 ◽  
Author(s):  
E. Jager ◽  
Y. Nagata ◽  
S. Gnjatic ◽  
H. Wada ◽  
E. Stockert ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cell Responses ◽  
Cellular Immune Responses ◽  
Cellular Immune

scholarly journals Resistance of Major Histocompatibility Complex Class B (MHC-B) to Nef-Mediated Downregulation Relative to that of MHC-A Is Conserved among Primate Lentiviruses and Influences Antiviral T Cell Responses in HIV-1-Infected Individuals

2017 ◽  
Vol 92 (1) ◽  
Author(s):  
Francis Mwimanzi ◽  
Mako Toyoda ◽  
Macdonald Mahiti ◽  
Jaclyn K. Mann ◽  
Jeffrey N. Martin ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Immune Responses ◽  
Complex Class ◽  
Subtype C ◽  
Cell Responses ◽  
Cellular Immune Responses ◽  
Histocompatibility Complex ◽  
Primate Lentiviruses ◽  
Cellular Immune ◽  
Hiv 1

ABSTRACTPatient-derived HIV-1 subtype B Nef clones downregulate HLA-A more efficiently than HLA-B. However, it remains unknown whether this property is common to Nef proteins across primate lentiviruses and how antiviral immune responses may be affected. We examined 263 Nef clones from diverse primate lentiviruses including different pandemic HIV-1 group M subtypes for their ability to downregulate major histocompatibility complex class A (MHC-A) and MHC-B from the cell surface. Though lentiviral Nef proteins differed markedly in their absolute MHC-A and MHC-B downregulation abilities, all lentiviral Nef lineages downregulated MHC-A, on average, 11 to 32% more efficiently than MHC-B. Nef genotype/phenotype analyses in a cohort of HIV-1 subtype C-infected patients (n= 168), together with site-directed mutagenesis, revealed Nef position 9 as a subtype-specific determinant of differential HLA-A versus HLA-B downregulation activity. Nef clones harboring nonconsensus variants at codon 9 downregulated HLA-B (though not HLA-A) significantly better than those harboring the consensus sequence at this site, resulting in reduced recognition of infected target cells by HIV-1-specific CD8+effector cellsin vitro. Among persons expressing protective HLA class I alleles, carriage of Nef codon 9 variants was also associated with reducedex vivoHIV-specific T cell responses. Our results demonstrate that Nef's inferior ability to downregulate MHC-B compared to that of MHC-A is conserved across primate lentiviruses and suggest that this property influences antiviral cellular immune responses.IMPORTANCEPrimate lentiviruses encode the Nef protein that plays an essential role in establishing persistent infection in their respective host species. Nef interacts with the cytoplasmic region of MHC-A and MHC-B molecules and downregulates them from the infected cell surface to escape recognition by host cellular immunity. Using a panel of Nef alleles isolated from diverse primate lentiviruses including pandemic HIV-1 group M subtypes, we demonstrate that Nef proteins across all lentiviral lineages downregulate MHC-A approximately 20% more effectively than MHC-B. We further identify a naturally polymorphic site at Nef position 9 that contributes to the MHC-B downregulation function in HIV-1 subtype C and show that carriage of Nef variants with enhanced MHC-B downregulation ability is associated with reduced breadth and magnitude of MHC-B-restricted cellular immune responses in HIV-infected individuals. Our study underscores an evolutionarily conserved interaction between lentiviruses and primate immune systems that may contribute to pathogenesis.

scholarly journals Cellular Immune Responses Associated with Occult Hepatitis C Virus Infection of the Liver

2006 ◽  
Vol 80 (22) ◽  
pp. 10972-10979 ◽  
Author(s):  
Juan A. Quiroga ◽  
Silvia Llorente ◽  
Inmaculada Castillo ◽  
Elena Rodríguez-Iñigo ◽  
Margarita Pardo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Responses ◽  
Hcv Infection ◽  
Hcv Rna ◽  
Occult Hepatitis ◽  
Cell Responses ◽  
Cellular Immune Responses ◽  
Cellular Immune ◽  
Occult Hepatitis C

ABSTRACT Occult hepatitis C virus (HCV) infection is a type of recently identified chronic infection that is evidenced only by detection of HCV RNA in liver; patients consistently test negative for antibodies to HCV and HCV RNA in serum. Using ex vivo and in vitro measures of T-cell responses, we have identified functional virus-specific memory CD4+ and CD8+ T cells in the peripheral blood of patients with occult HCV infection. The features of the virus-specific T cells were consistent with immune surveillance functions, supporting previous exposure to HCV. In addition, the magnitudes of CD4+ and CD8+ T-cell responses were in parallel and correlated inversely with the extent of liver HCV infection. The detection of HCV-specific T cells in individuals in whom HCV RNA can persist in the liver despite the absence of viremia and antibodies indicates that HCV replication is prolonged in the face of virus-specific CD4+ and CD8+ T-cell responses. These findings demonstrate that HCV-specific cellular immune responses are markers not only of previous exposure to and recovery from HCV but also of ongoing occult HCV infection.

scholarly journals Recombinant Proteins of Cryptosporidium parvum Induce Proliferation of Mesenteric Lymph Node Cells in Infected Mice

2005 ◽  
Vol 73 (8) ◽  
pp. 5245-5248 ◽  
Author(s):  
Inderpal Singh ◽  
Cynthia Theodos ◽  
Saul Tzipori
Keyword(s):  
Lymph Node ◽  
Immune Responses ◽  
Recombinant Proteins ◽  
Cryptosporidium Parvum ◽  
Mesenteric Lymph Node ◽  
Recombinant Antigens ◽  
Cellular Immune Responses ◽  
Mesenteric Lymph ◽  
Lymph Node Cells ◽  
Cellular Immune

ABSTRACT Recombinant antigens of Cryptosporidium parvum, Cp900 and Cp40 but not Cp15, stimulated C. parvum-specific proliferative immune responses of mesenteric lymph node cells in C57BL/6J mice infected with different isolates (MD, GCH1, UCP, and IOWA) of C. parvum, indicating that both Cp900 and Cp40 are immunodominant targets of cellular immune responses during C. parvum infection.

scholarly journals Control of SARS-CoV-2 infection after Spike DNA or Spike DNA+Protein co-immunization in rhesus macaques

2021 ◽  
Author(s):  
Margherita Rosati ◽  
Mahesh Agarwal ◽  
Xintao Hu ◽  
Santhi Devasundaram ◽  
Dimitris Stellas ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Protective Efficacy ◽  
Rhesus Macaques ◽  
Neutralizing Antibody ◽  
Anatomical Site ◽  
Cell Responses ◽  
Cellular Immune Responses ◽  
Antibody Titers ◽  
Cellular Immune

The speed of development, versatility and efficacy of mRNA-based vaccines have been amply demonstrated in the case of SARS-CoV-2. DNA vaccines represent an important alternative since they induce both humoral and cellular immune responses in animal models and in human trials. We tested the immunogenicity and protective efficacy of DNA-based vaccine regimens expressing different prefusion-stabilized SARS-CoV-2 Spike antigens upon intramuscular injection followed by electroporation in rhesus macaques. Different Spike DNA vaccine regimens induced antibodies that potently neutralized SARS-CoV-2 in vitro and elicited robust T cell responses. The DNA-only vaccine regimens were compared to a regimen that included co-immunization of Spike DNA and protein in the same anatomical site, the latter of which showed significant higher antibody responses. All vaccine regimens led to control of SARS-CoV-2 intranasal/intratracheal challenge and absence of virus dissemination to the lower respiratory tract. Vaccine-induced binding and neutralizing antibody titers and antibody-dependent cellular phagocytosis inversely correlated with transient virus levels in the nasal mucosa. Importantly, the Spike DNA+Protein co-immunization regimen induced the highest binding and neutralizing antibodies and showed the strongest control against SARS-CoV-2 challenge in rhesus macaques.

Sign in / Sign up

Export Citation Format

Share Document