55 research outputs found
Peripheral cytokine levels differ by HPV status and change treatment-dependently in patients with head and neck squamous cell carcinoma
Cytokines and immune mediators play an important role in the communication between immune cells guiding their response to infectious diseases or cancer. In this study, a comprehensive longitudinal analysis of serum cytokines and immune mediators in head and neck squamous cell carcinoma (HNSCC) patients was performed. In a prospective, non-interventional, longitudinal study, blood samples from 22 HNSCC patients were taken at defined time points (TP) before, during, and every 3 months after completion of (chemo)radio)therapy (CRT/RT) until 12 months after treatment. Serum concentrations of 17 cytokines/immune mediators and High-Mobility-Group-Protein B1 (HMGB1) were measured by fluorescent bead array and ELISA. Concentrations of sFas were significantly elevated during and after CRT/RT, whereas perforin levels were significantly decreased after CRT/RT. Levels of MIP-1β and Granzyme B differed significantly during CRT/RT by HPV status. Increased HMGB1 levels were observed at recurrence, accompanied by high levels of IL-4 and IL-10. The sFas increase and simultaneous perforin decrease may indicate an impaired immune cell function during adjuvant radiotherapy. Increased levels of pro-inflammatory cytokines in HPV+ compared to HPV− patients seem to reflect the elevated immunogenicity of HPV-positive tumors. High levels of HMGB1 and anti-inflammatory cytokines at recurrence may be interpreted as a sign of immune evasion
The Human Leukocyte Antigen-DPB1 Degree of Compatibility Is Determined by Its Expression Level and Mismatch Permissiveness: A German Multicenter Analysis
T-cell epitope matching according to the TCE3 algorithm classifies HLA-DPB1 mismatches in permissive and non-permissive. This classification has been shown to be predictive for mortality and acute GvHD (aGvHD) events in large international cohorts. We retrospectively genotyped HLA-DPB1 in 3523 patients transplanted in Germany between 2000 and 2014 and in their unrelated donors using an Illumina amplicon-NGS based assay. Aim of the study was to evaluate DP-compatibility beyond the established TCE3 algorithm by assessing the combined effect of several DP-mismatch parameters on post-transplant outcome. We implemented an extended DP-mismatch assessment model where TCE3, DP allotype expression with respect to rs9277534, mismatch vector and number of mismatches were conjointly taken into consideration. In this model, non-permissive HLA-DPB1 mismatches showed significantly increased aGvHD risk if they were accompanied by two HLA-DPB1 mismatches in GvH direction (HR: 1.46) or one mismatched highly expressed patient allotype (HR: 1.53). As previously reported, non-permissive HLA-DPB1 mismatches associated with a significantly higher risk of aGvHD and non-relapse mortality (HR 1.36 and 1.21, respectively), which in turn translated into worse GvHD and relapse free survival (HR 1.13). Effects on GvL and GvHD appeared strongest in GvH-directed non-permissive mismatches. Our study results support the consideration of additional HLA-DPB1 mismatch parameters along with the established TCE3 matching algorithm for refinement of future donor selection. In particular, our findings suggest that DP non-permissiveness associated with two HLA-DPB1 mismatches or at least on highly expressed mismatched patient allotype should be avoided
Donor HLA-E Status Associates with Disease-Free Survival and Transplant-Related Mortality after Non In Vivo T Cell-Depleted HSCT for Acute Leukemia
Previous studies have suggested that HLA-E may have a significant role in the outcome of matched unrelated hematopoietic stem cell transplantation (HSCT), especially for patients with acute leukemia. We used Center for International Blood and Marrow Transplant Research data and samples of 1840 adult patients with acute leukemia and their 10/10 HLA-matched unrelated donors to investigate the impact of HLA-E matching status as well as of donor/recipient (D/R) HLA-E genotype on post-HSCT outcome. Both patients and donors were HLA-E genotyped by next-generation sequencing. All patients received their first transplant in complete remission between 2000 and 2015. Median follow-up time was 90 months. Overall survival, disease-free survival (DFS), transplant-related mortality (TRM), and relapse incidence were primary endpoints with statistical significance set at .01. D/R HLA-E genotype analysis revealed a significant association of donor HLA-E*01:03/01:03 genotype with DFS (hazard ratio [HR] = 1.35, P = .0006) and TRM (HR= 1.41, P = .0058) in patients who received T cell replete (ie, without in vivo T cell depletion) transplants (n = 1297). As for D/R HLA-E matching, we did not identify any significant effect on any of the clinical outcome endpoints. In conclusion, this is the largest study to date reporting an improvement of DFS and TRM after matched unrelated HSCT by avoidance of HLA-E*01:03 homozygous donors in patients transplanted with T cell replete grafts for acute leukemia
HLA-DRB3/4/5 Matching Improves Outcome of Unrelated Hematopoietic Stem Cell Transplantation
The HLA-DRB3/4/5 loci are closely linked to the HLA-DRB1 gene. Mismatches in these
loci occur with a frequency of about 8%–12% in otherwise 10/10 HLA-matched transplant
pairs. There is preliminary evidence that these disparities may associate with increased
acute graft-versus-host disease (GvHD) rates. The aim of this study was to analyze a large
cohort of German patients and their donors for HLA-DRB3/4/5 compatibility and to
correlate the HLA-DRB3/4/5 matching status with the outcome of unrelated
hematopoietic stem cell transplantation (uHSCT). To this end, 3,410 patients and their
respective donors were HLA-DRB3/4/5 and HLA-DPB1 typed by amplicon-based nextgeneration
sequencing (NGS). All patients included received their first allogeneic
transplant for malignant hematologic diseases between 2000 and 2014. Mismatches in
the antigen recognition domain (ARD) of HLA-DRB3/4/5 genes were correlated with
clinical outcome. HLA-DRB3/4/5 incompatibility was seen in 12.5% (n = 296) and 17.8%
(n = 185) of the 10/10 and 9/10 HLA-matched cases, respectively. HLA-DRB3/4/5
mismatches in the ARD associated with a worse overall survival (OS), as shown in
univariate (5-year OS: 46.1% vs. 39.8%, log-rank p = 0.038) and multivariate analyses
[hazard ratio (HR) 1.25, 95% CI 1.02–1.54, p = 0.034] in the otherwise 10/10 HLAmatched
subgroup. The worse outcome was mainly driven by a significantly higher nonrelapse
mortality (HR 1.35, 95% CI 1.05–1.73, p = 0.017). In the 9/10 HLA-matched
cases, the effect was not statistically significant. Our study results suggest that
mismatches within the ARD of HLA-DRB3/4/5 genes significantly impact the outcome
of otherwise fully matched uHSCT and support their consideration upon donor selection in
the future
HLA-DRB3/4/5 Matching Improves Outcome of Unrelated Hematopoietic Stem Cell Transplantation
The HLA-DRB3/4/5 loci are closely linked to the HLA-DRB1 gene. Mismatches in these
loci occur with a frequency of about 8%–12% in otherwise 10/10 HLA-matched transplant
pairs. There is preliminary evidence that these disparities may associate with increased
acute graft-versus-host disease (GvHD) rates. The aim of this study was to analyze a large
cohort of German patients and their donors for HLA-DRB3/4/5 compatibility and to
correlate the HLA-DRB3/4/5 matching status with the outcome of unrelated
hematopoietic stem cell transplantation (uHSCT). To this end, 3,410 patients and their
respective donors were HLA-DRB3/4/5 and HLA-DPB1 typed by amplicon-based nextgeneration
sequencing (NGS). All patients included received their first allogeneic
transplant for malignant hematologic diseases between 2000 and 2014. Mismatches in
the antigen recognition domain (ARD) of HLA-DRB3/4/5 genes were correlated with
clinical outcome. HLA-DRB3/4/5 incompatibility was seen in 12.5% (n = 296) and 17.8%
(n = 185) of the 10/10 and 9/10 HLA-matched cases, respectively. HLA-DRB3/4/5
mismatches in the ARD associated with a worse overall survival (OS), as shown in
univariate (5-year OS: 46.1% vs. 39.8%, log-rank p = 0.038) and multivariate analyses
[hazard ratio (HR) 1.25, 95% CI 1.02–1.54, p = 0.034] in the otherwise 10/10 HLAmatched
subgroup. The worse outcome was mainly driven by a significantly higher nonrelapse
mortality (HR 1.35, 95% CI 1.05–1.73, p = 0.017). In the 9/10 HLA-matched
cases, the effect was not statistically significant. Our study results suggest that
mismatches within the ARD of HLA-DRB3/4/5 genes significantly impact the outcome
of otherwise fully matched uHSCT and support their consideration upon donor selection in
the future
The HLA ligandome of oropharyngeal squamous cell carcinomas reveals shared tumour-exclusive peptides for semi-personalised vaccination
Background
The immune peptidome of OPSCC has not previously been studied. Cancer-antigen specific vaccination may improve clinical outcome and efficacy of immune checkpoint inhibitors such as PD1/PD-L1 antibodies.
Methods
Mapping of the OPSCC HLA ligandome was performed by mass spectrometry (MS) based analysis of naturally presented HLA ligands isolated from tumour tissue samples (n = 40) using immunoaffinity purification. The cohort included 22 HPV-positive (primarily HPV-16) and 18 HPV-negative samples. A benign reference dataset comprised of the HLA ligandomes of benign haematological and tissue datasets was used to identify tumour-associated antigens.
Results
MS analysis led to the identification of naturally HLA-presented peptides in OPSCC tumour tissue. In total, 22,769 peptides from 9485 source proteins were detected on HLA class I. For HLA class II, 15,203 peptides from 4634 source proteins were discovered. By comparative profiling against the benign HLA ligandomic datasets, 29 OPSCC-associated HLA class I ligands covering 11 different HLA allotypes and nine HLA class II ligands were selected to create a peptide warehouse.
Conclusion
Tumour-associated peptides are HLA-presented on the cell surfaces of OPSCCs. The established warehouse of OPSCC-associated peptides can be used for downstream immunogenicity testing and peptide-based immunotherapy in (semi)personalised strategies
Missing KIR-Ligands in Single Mismatched Unrelated Hematopoietic Stem Cell Transplantation
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