scholarly journals High TIL, HLA, and Immune Checkpoint Expression in Conventional High-Grade and Dedifferentiated Chondrosarcoma and Poor Clinical Course of the Disease

2021 ◽  
Vol 11 ◽  
Author(s):  
Sjoerd P. F. T. Nota ◽  
Ahmad Al-Sukaini ◽  
Shalin S. Patel ◽  
Francesco Sabbatino ◽  
G. Petur Nielsen ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Rational Design ◽  
Tumor Antigens ◽  
Clinical Course ◽  
Tumor Infiltrating Lymphocytes ◽  
Hla Class I ◽  
Class I ◽  
Immune Recognition ◽  
Tumor Infiltration ◽  
Dedifferentiated Chondrosarcoma

PurposeThe aim of this study was to characterize chondrosarcoma tumor infiltration by immune cells and the expression of immunologically relevant molecules. This information may contribute to our understanding of the role of immunological events in the pathogenesis of chondrosarcoma and to the rational design of immunotherapeutic strategies.Patients and MethodsA tissue microarray (TMA) containing 52 conventional and 24 dedifferentiated chondrosarcoma specimens was analyzed by immunohistochemical staining for the expression of parameters associated with tumor antigen-specific immune responses, namely, CD4+ and CD8+ tumor infiltrating lymphocytes (TILs) and the expression of HLA class I heavy chain, beta-2 microglobulin (β2m), HLA class II and immune checkpoint molecules, B7-H3 and PD-1/PD-L1. The results were correlated with histopathological characteristics and the clinical course of the disease.ResultsCD8+ TILs were present in 21% of the conventional and 90% of the dedifferentiated chondrosarcoma tumors tested. B7-H3 was expressed in 69% of the conventional and 96% of the dedifferentiated chondrosarcoma tumors tested. PD-1 and PD-L1 were expressed 53% and 33% respectively of the dedifferentiated tumors tested. PD-L1 expression was associated with shorter time to metastasis.ConclusionThe tumor infiltration by lymphocytes suggests that chondrosarcoma is immunogenic. Defects in HLA class I antigen and expression of the checkpoint molecules B7-H3 and PD-1/PD-L1 suggest that tumor cells utilize escape mechanisms to avoid immune recognition and destruction. This data implies that chondrosarcoma will benefit from strategies that enhance the immunogenicity of tumor antigens and/or counteract the escape mechanisms.

scholarly journals Selective Histocompatibility Leukocyte Antigen (Hla)-A2 Loss Caused by Aberrant Pre-mRNA Splicing in 624mel28 Melanoma Cells

1999 ◽  
Vol 190 (2) ◽  
pp. 205-216 ◽  
Author(s):  
Zhigang Wang ◽  
Francesco M. Marincola ◽  
Licia Rivoltini ◽  
Giorgio Parmiani ◽  
Soldano Ferrone
Keyword(s):  
Hla Class I ◽  
Melanoma Cells ◽  
Class I ◽  
Splice Donor Site ◽  
Immune Recognition ◽  
Translation Efficiency ◽  
Exon 2 ◽  
Leukocyte Antigen ◽  
Allele Loss ◽  
Intron 2

Histocompatibility leukocyte antigen (HLA)-A2 is used as a restricting element to present several melanoma-associated antigen (MAA)-derived peptides to cytotoxic T lymphocytes (CTLs). HLA-A2 antigen is selectively lost in primary melanoma lesions and more frequently in metastases. Only scanty information is available about the molecular mechanisms underlying this abnormality, in spite of its potentially negative impact on the clinical course of the disease and on the outcome of T cell–based immunotherapy. Therefore, in this study we have shown that the selective HLA-A2 antigen loss in melanoma cells 624MEL28 is caused by a splicing defect of HLA-A2 pre-mRNA because of a base substitution at the 5′ splice donor site of intron 2 of the HLA-A2 gene. As a result, HLA-A2 transcripts are spliced to two aberrant forms, one with exon 2 skipping and the other with intron 2 retention. The latter is not translated because of an early premature stop codon in the retained intron. In contrast, the transcript with exon 2 skipping is translated to a truncated HLA-A2 heavy chain without the α1 domain. Such a polypeptide is synthesized in vitro but is not detectable in cells, probably because of the low steady state level of the corresponding mRNA and the low translation efficiency. These results indicate that a single mutational event in an HLA class I gene is sufficient for loss of the corresponding allele. This may account, at least in part, for the high frequency of selective HLA class I allele loss in melanoma cells. Our conclusion emphasizes the need to implement active specific immunotherapy with a combination of peptides presented by various HLA class I alleles. This strategy may counteract the ability of melanoma cells with selective HLA class I allele loss to escape from immune recognition.

Determination of the immunogenetic risk of developing cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e13132-e13132
Author(s):  
István Miklós ◽  
Eniko Rita Toke ◽  
Mónika Megyesi ◽  
Levente Molnar ◽  
József Tóth ◽  
...  
Keyword(s):  
T Cell ◽  
General Population ◽  
Cancer Risk ◽  
Tumor Antigens ◽  
Hla Class I ◽  
Class I ◽  
P Value ◽  
T Cell Epitopes ◽  
Risk Of Cancer

e13132 Background: Association between certain HLA types and cancer is well known. We hypothesized that the number of epitopes of tumor antigens presented by autologous HLAs characterizes a patient’s capacity to kill tumor cells. These CD8+ T cell epitopes are presented by 6 out of >13,000 known HLA class I alleles and induce extremely variable tumor-specific T-cell responses. Methods: We predicted HLA-binding epitopes from 48 frequently expressed tumor antigens in subjects characterized with 6 HLA class I alleles. To develop the “HLA Score” cancer risk predictor we used epitopes binding to multiple HLAs of a subject. The predictor was trained on 5,789 non-American subjects. To identify populations with high and low immunogenetic risk to develop cancer we compared the HLA Score of American cancer subjects to a general population of American subjects (1,400 subjects). The performance of the predictor was characterized with AUC and Risk Ratio. Due to Bonferroni correction, AUC values with p-value p<0.007 was accepted as significant. Results: “HLA Score” predictor significantly separated cancer patients from the general population in six out of the seven investigated cancer types. The Risk Ratios between the most protected and most at risk subpopulations ranged between 2.38 and 5.67 (Table). Cancer risk prediction with HLA Score. Conclusions: Subjects with certain HLA class I alleles have high risk of developing cancer. The novel “HLA Score” predictor we introduced here could complement current testing used for determination of the genetic risk of cancer.[Table: see text]

HLA class-I-restricted and tumor-specific CTL in tumor-infiltrating lymphocytes of patients with gastric cancer

1997 ◽  
Vol 70 (6) ◽  
pp. 631-638 ◽  
Author(s):  
Tomoaki Hoshino ◽  
Naoko Seki ◽  
Megumi Kikuchi ◽  
Terukazu Kuramoto ◽  
Osamu Iwamoto ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Tumor Infiltrating Lymphocytes ◽  
Hla Class I ◽  
Class I ◽  
Infiltrating Lymphocytes

scholarly journals HLA class I restricted epitopes prediction of common tumor antigens in Caucasoid and Oriental ethnic populations: implication on antigen selection for tumor specific CD8+ T cellular immunotherapy and cancer vaccine design

2019 ◽  
Author(s):  
Wei Hu ◽  
He Meifang ◽  
Li Liangping
Keyword(s):  
Tumor Antigen ◽  
Tumor Antigens ◽  
Therapeutic Vaccine ◽  
Vaccine Design ◽  
Hla Class I ◽  
The Cancer Genome Atlas ◽  
Class I ◽  
Cellular Immunotherapy ◽  
Hla Class I Molecules ◽  
Two Populations

Abstract Background Tumor antigens processed and presented by human leukocyte antigen (HLA) Class I alleles are important targets in tumor immunotherapy. Clinical trials showed that CD8+ T cells specific to tumor associated antigens (TAAs) and tumor neoantigens is one of the main factors resulting tumor regression. Affinity prediction of tumor antigen epitopes to HLA is an important reference index for peptide selection which is highly individualized. Results In this study, we selected 6 CTAs (cancer-testis antigens) commonly used in cancer immunotherapy and top 95 hot mutations from the Cancer Genome Atlas for analyzing potential epitopes with high affinities to the common HLA class I molecules in Caucasoid and Oriental ethnic population respectively. The results showed that the overall difference of CTAs epitope prediction is small between the two populations. Meanwhile, there is a linear relationship between the CTAs peptide length and the relative overall epitope occurrence. However, the difference is bigger for epitopes prediction of missense mutations between the two populations. It’s worth noting that, both in the two populations, the single point mutations with the highest incidences have the lowest epitope occurrence while the mutations with the highest epitope occurrence are with low mutation incidence. This may be the result of long-term selection by the host immunosurveillance. The characteristic of predicted epitopes of frameshift / inframe insertion mutations was approximately halfway between the other two antigens above. Conclusion Our results provide clues for tumor antigen and epitope selection in specific CD8+ T cellular immunotherapy and cancer therapeutic vaccine design.

The CD38-Positive and CD38-Negative Subsets of CD34(high)-Positive Primary Acute Myeloid Leukemia Blasts Differ Considerably in the Expression of Immune Recognition Molecules

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2936-2936
Author(s):  
Eva Distler ◽  
Anna Jürchott ◽  
Abdo Konur ◽  
Astrid Schneider ◽  
Eva M. Wagner ◽  
...  
Keyword(s):  
Transferrin Receptor ◽  
Myeloid Leukemia ◽  
Hla Class I ◽  
Class I ◽  
Immune Recognition ◽  
Immunodeficient Mice ◽  
Hla Dr ◽  
Kit Receptor ◽  
Lineage Markers ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) is thought to arise from a rare putative ‘leukemic stem cell’ that is capable of self-renewal and formation of leukemic blasts. Serial xenotransplantation studies in immunodeficient mice have shown that this leukemia-initiating cell resides at very low numbers within CD34(high)-positive CD38-negative AML cells. Thus, immunotherapeutic approaches successfully eradicating this cell compartment should result in cure from disease. The objective of our study was to characterize the immune phenotype of the CD38-negative and CD38-positive subsets of primary CD34(high)-positive AML blasts ex vivo. We obtained therapeutic leukapheresis products from 17 AML patients of FAB M0-M5 subtypes with white blood cell counts exceeding 10^11/L at primary diagnosis. These products were used to purify CD34-positive cells by immunomagnetic microbeads. CD34(high)-expressing cells were subsequently sorted by flow cytometry into CD38-negative and CD38-positive subsets, respectively. Both fractions were then phenotyped with fluorochrome-conjugated monoclonal antibodies for expression of surface markers previously described to differ between leukemic blasts and stem cells, i.e. CD71 (transferrin receptor), CD90 (Thy-1), CD117 (c-kit receptor), CD123 (IL3Ralpha), CD44, and CD11c. We also included markers relevant for recognition by natural killer cells and T cells, namely HLA class I, HLA-DR, CD40, CD54 (ICAM-1), CD58 (LFA-3), CD80 (B7.1), and CD86 (B7.2), as well as the lineage markers CD2, CD3, CD4, CD7, CD8, CD10, CD14, CD19, CD20, and CD56. Our results demonstrated that the CD38-positive and CD38-negative subsets of CD34(high)-positive AML blasts differed considerably in the expression of CD58, CD71, CD86, CD117, and HLA class I. Although these markers were detected on both subsets, the mean fluorescence intensity (MFI) values were lower in the CD38-negative compartment compared to the CD38-positive counterpart (medians: CD58, 1335 versus 1933; CD71, 657 versus 811; CD86, 746 versus 753; CD117, 490 versus 758; HLA class I, 4431 versus 6000). We compared the MFI values of both cell subsets with the Wilcoxon signed-rank test. P-values below 5% were detected for CD58 (p=0.005), CD71 (p=0.003), CD86 (p=0.041), CD117 (p=0.009), and HLA class I (p=0.011), respectively. The CD38-positive and CD38-negative subsets showed comparable intense staining for CD11c, CD44, CD54, CD123, and HLA-DR. In contrast, CD90, CD80, CD40, and the lineage markers were negative in both fractions. We concluded from these results that primary CD34(high)-positive CD38-negative AML blasts containing small numbers of leukemia-initiating cells expressed overall lower levels of the immune recognition molecules CD58 (LFA-3), CD86 (B7.2), and HLA class I compared to their CD38-positive counterparts. However, all CD34(high)-positive CD38-negative AML cells showed detectable HLA class I expression on the cell surface, making them accessible to T-cell based immunotherapies. In line with previous data, CD71 (transferrin receptor) and CD117 (c-kit receptor) were observed at reduced levels on CD34(high)-positive CD38-negative AML cells. Ongoing functional studies explore if the CD38-negative and CD38-positive subsets of CD34(high)-positive AML blasts differ in the immunogenicity for leukemia-reactive CD4 and CD8 T cells, both in vitro as well as in immunodeficient mice in vivo.

scholarly journals An innovative approach for HLA typing, molecular tumor testing and the validation of tumor exclusive antigens

2020 ◽  
Author(s):  
Michael Ghosh ◽  
Leon Bichmann ◽  
Jonas Scheid ◽  
Gizem Güler ◽  
Heiko Schuster ◽  
...  
Keyword(s):  
Machine Learning ◽  
Tumor Antigens ◽  
Internal Standard ◽  
Hla Class I ◽  
Hla Typing ◽  
Class I ◽  
Data Sets ◽  
Peptide Motifs ◽  
Versatile Tool ◽  
Specific Antigens

AbstractThe immunopeptidome, representing the point of contact between somatic and T cells, is key for adaptive immunity. Each presented peptide holds an abundance of information not yet well understood. Up to now, the scientific focus has been the definition of pathogenic or tumor derived epitopes and the deconvolution of HLA peptide motifs of the entire immunopeptidome. Here we go one step further and assess the properties of individual peptides to identify defined HLA allotype-specific and frequently presented peptides. Such allotypic peptides represent a versatile tool to determine HLA allotypes or serve as internal standard for characterization of cancer antigens and differentially processed antigens. Finally, individual tissue- and dignity-specific antigens were defined, and the latter were successfully implemented for molecular tumor testing.Using mass spectrometry based immunopeptidomics a database was generated consisting of ∼900 HLA-typed samples. The identified allotypic peptides enabled a HLA class I allotype determination, which was 95% correct in our in-house dataset and 98% in an external dataset. These abundant peptides were implemented as internal standard for a semi-quantitative investigation of established tumor antigens and antigens processed differentially in malignant and benign tissue. Defined dignity-specific antigens allowed a 87% correct tumor detection across numerous tumor types.In summary, we describe a machine learning approach for mining immunopeptidomic data in order to develop a classification method, allowing to differentiate HLA class I-allotypes of a sample or distinguish between healthy and malignant state of tissues. Furthermore, based on this method, we developed a procedure for the validation of tumor exclusive antigens. Our results support classification of immunopeptidomic data sets using machine learning and highlight their potential utility for biomarker development.

812 PROGRAMMED CELL DEATH PROTEIN 1/PROGRAMMED DEATH LIGAND 1 AND HLA-CLASS I ARE POTENTIAL THERAPEUTIC TARGETS IN ESOPHAGEAL NEUROENDOCRINE CARCINOMA

2021 ◽  
Vol 34 (Supplement_1) ◽  
Author(s):  
Satoshi Ya Masthita ◽  
Hiroyuki Abe ◽  
Hiroharu Yamashita ◽  
Koichi Yagi ◽  
Yasuyuki Seto ◽  
...  
Keyword(s):  
Neuroendocrine Carcinoma ◽  
Therapeutic Targets ◽  
Tumor Infiltrating Lymphocytes ◽  
Hla Class I ◽  
Class I ◽  
Neuroendocrine Neoplasm ◽  
Programmed Death ◽  
Positive Score ◽  
Combined Positive Score ◽  
Infiltrating Lymphocytes

Abstract   Esophageal neuroendocrine carcinoma (NEC) is a rare and aggressive subtype with a poor prognosis. Pembrolizumab was recommended for the treatment of PD-L1 positive tumors in esophageal cancer and the combined positive score (CPS) was reported to be a better predictor of efficacy compared to the tumor proportion score (TPS). We investigated the expression profile of potential therapeutic targets (PD-L1, HLA class I, Mismatch repair (MMR) proteins) and tumor infiltrating lymphocytes (TILs) in esophageal NEC. Methods 15 NECs of the esophagus including mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) with squamous cell carcinoma (SCC) component were investigated in the study. The expression of PD-L1 (quantitatively evaluated by CPS and TPS), HLA class I, and MMR protein expression were examined immunohistochemically. TIL abundance was examined semiquantitatively by observation of H&E slides. Results Nine (60%) showed a CPS ≥ 1, five (33%) showed a CPS ≥10, and five cases showed a TPS ≥1. Survival analysis showed a significantly longer overall survival in the CPS ≥1 group than in the CPS &lt;1 group. Deficiency of MMR protein was not observed in any cases. HLA-Class I expression was retained in 10 (67%), and loss of HLA-Class I was significantly correlated with frequent lymph node metastasis, high TNM Stage, and low TIL. Three showed both PD-L1 CPS ≥ 10 and high TIL. Conclusion In esophageal NEC, PD-L1 positivity and preserved HLA-Class I expression were frequently observed, and PD-L1 CPS ≥ 1 was significantly associated with the better prognosis of esophageal NEC. Therefore, the PD-1/PD-L1 pathway and HLA-class I are thought to be potential therapeutic targets in esophageal neuroendocrine carcinoma.

Sign in / Sign up

Export Citation Format

Share Document