MHC Class I molecule
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MHC class I downregulation is a general mechanism by which tumor cells can escape from T-cell-mediated immunity. This downregulation also represents a serious obstacle to the development of effective antitumor immunotherapy or vaccination. Therefore, successful immunotherapeutic and vaccination protocols should be optimized against tumors with distinct cell surface expression of the MHC class I molecules. Mechanisms leading to protective immunity may vary in different models with respect to the particular tumors (e.g., in their levels of residual expression of the MHC class I molecules on tumor cells or inducibility of MHC class I expression). Notably, both CD8(+) cell-mediated immunity and MHC class I-unrestricted mechanisms can take place against MHC class I-deficient tumors. Since MHC class I downregulation is frequently reversible by cytokines and also by the activation of epigenetically silenced genes, an attractive strategy is to elicit specific cell-mediated immunity combined with restoration of MHC class I expression on tumor cells.
- MeSH
- imunoterapie metody MeSH
- lidé MeSH
- MHC antigeny I. třídy biosyntéza imunologie MeSH
- nádory imunologie terapie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
MHC class I presentation of short peptides enables CD8+ T cell (TCD8+) immunosurveillance of tumors and intracellular pathogens. A key feature of the class I pathway is that the immunopeptidome is highly skewed from the cellular degradome, indicating high selectivity of the access of protease-generated peptides to class I molecules. Similarly, in professional antigen-presenting cells, peptides from minute amounts of proteins introduced into the cytosol outcompete an overwhelming supply of constitutively generated peptides. Here, we propose that antigen processing is based on substrate channeling and review recent studies from the antigen processing and cell biology fields that provide a starting point for testing this hypothesis.
- MeSH
- adaptivní imunita imunologie MeSH
- antigen prezentující buňky imunologie MeSH
- CD8-pozitivní T-lymfocyty imunologie MeSH
- imunitní dozor imunologie MeSH
- lidé MeSH
- MHC antigeny I. třídy imunologie MeSH
- peptidy imunologie MeSH
- prezentace antigenu imunologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Research Support, N.I.H., Intramural MeSH
The therapy of different advanced-stage malignancies with monoclonal antibodies blocking programmed cell death protein 1 (PD-1)/PD-1 ligand 1 (PD-L1) signaling has had an impressive long-lasting effect in a portion of patients, but in most cases, this therapy was not successful, or a secondary resistance developed. To enhance its efficacy in treated patients, predictive biomarkers are searched for and various combination treatments are intensively investigated. As the downregulation of major histocompatibility complex (MHC) class I molecules is one of the most frequent mechanisms of tumor escape from the host's immunity, it should be considered in PD-1/PD-L1 checkpoint inhibition. The potential for the use of a PD-1/PD-L1 blockade in the treatment of tumors with aberrant MHC class I expression is discussed, and some strategies of combination therapy are suggested.
- MeSH
- antigeny CD274 antagonisté a inhibitory imunologie MeSH
- antigeny CD279 antagonisté a inhibitory imunologie MeSH
- down regulace * MeSH
- geny MHC třídy I MeSH
- imunoterapie metody MeSH
- lidé MeSH
- MHC antigeny I. třídy genetika MeSH
- monoklonální protilátky terapeutické užití MeSH
- nádory genetika imunologie terapie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
The accumulation of protein aggregates is toxic and linked to different diseases such as neurodegenerative disorders, but the role of the immune system to target and destroy aggregate-carrying cells is still relatively unknown. Here we show a substrate-specific presentation of antigenic peptides to the direct MHC class I pathway via autophagy. We observed no difference in presentation of peptides derived from the viral EBNA1 protein following suppression of autophagy by knocking down Atg5 and Atg12. However, the same knock down treatment suppressed the presentation from ovalbumin. Fusing the aggregate-prone poly-glutamine (PolyQ) to the ovalbumin had no effect on antigen presentation via autophagy. Interestingly, fusing the EBNA1-derived gly-ala repeat (GAr) sequence to ovalbumin rendered the presentation Atg5/12 independent. We also demonstrate that the relative levels of protein expression did not affect autophagy-mediated antigen presentation. These data suggest a substrate-dependent presentation of antigenic peptides for the MHC class I pathway via autophagy and indicate that the GAr of the EBNA1 illustrates a novel virus-mediated mechanism for immune evasion of autophagy-dependent antigen presentation.
Východisko. Solubilní HLA (sHLA) molekuly jsou sérovou formou HLA glykoproteinů, které kromě dalších funkcí hrají úlohu při transplantacích. Cílem naší práce bylo potvrdit možnost využití stanovení sHLA I. třídy k predikci a sledování průběhu GVHR (graft versus host reaction, reakce štěpu proti hostiteli) u dětí při transplantaci kostní dřeně (TDK). Metody a výsledky. Vyšetřili jsme u 6 pacientů sHLA I. třídy před a opakovaně po alogenní TKD. Transplantace byla provedena pro těžký kombinovaný imunodeficit u 1 dítěte, u 3 dětí pro akutní lymfoblastickou leukémii, 1 pacient byl transplantován pro těžkou aplastickou anémii a 1 pro non-Hodgkinský lymfom. Děti byly sledovány 15 dní až 21 měsíců podle svého klinického průběhu. S cílem zlepšení predikce možné GVHR před TKD jsme vyšetřili sHLA I. třídy v supernatantech získaných ze směsných lymfocytárních kultur (MLC) u 5 dětí transplantovaných pro akutní lymfatickou leukémii (ALL) a výsledky jsme porovnali s následnou GVHR klasifikovanou dle Seattle kritérií. Solubilní HLA molekuly I. třídy byly stanovovány metodou ELISA. Vzestup hladiny sHLA molekul předcházel o 1-2 dny projevy GVHR, nebylo však jednoznačně možné odlišit tento vzestup od případného výkyvu v hladinách z jiných příčin. Jeden případ hyperakutní GVHR III. stupně nebyl provázen žádnou odezvou v hladinách sHLA. Výsledky sHLA v supernatantech MLC byly individuální a neodpovídaly ani současně měřeným hladinám cytokinů ani stupni GVHR. Ve dvou případech s letálním průběhem přesto, že dárcem byl HLA identický sourozenec, byly nalezeny vysoké hodnoty sHLA v kultuře dárcovských lymfocytů. Závěry. Domníváme se, že výsledky sHLA I. třídy v souvislosti s predikcí GVHR je třeba interpretovat s velkou opatrností. V mozaice skládající se z klinického obrazu a dalších laboratorních vyšetření mohou tyto výsledky přispívat celkovému obrazu GVHR.
Background. sHLA molecules are the soluble forms of their membrane bound counterparts. sHLA class I. were recently reported to be a useful marker in the prediction of graft versus host reaction (GVHR) in adults. To confirm these presumptions in children we measured sHLA class I. serum levels in children after allogeneic bone marrow transplantation (BMT). We also investigated the levels of sHLA in the supernatants of mixed lymphocyte cultures (MLC) as possible predictors of GVHR prior to BMT. Methods and Results. Group of 6 investigated children included 1 child with severe combined immunodeficiency, 3 children with acute lymphoblastic leukemia, 1 with severe combined immunodeficiency, 3 children with acute lymphoblastic leukemia, 1 with severe aplastic anemia and 1 with non Hodgkin lymphoma. The period of follow up varied from 15 days to 21 months according to the course of the disease. In the prediction of GVHR the levels of sHLA were measured in 5 children with acute leukemia in supernatants of MLC and the results were compared with the grade of GVHR classified according Seattle criteria. Soluble HLA class I. molecules were evaluated by ELISA. Rise of the levels of sHLA preceded 1-2 days the clinical signs of GVHR, however, it could not be distinguished from the occasional rise of a different cause. The levels of sHLA found in the supernatants of MLC showed individual results, which did not correspond to the level of cytokines in the same culture, or to the grade of GVHR observed. However, twice higher levels of sHLA in the culture of donor lymphocytes correlated with the lethal outcome of GVHR despite the fact that the donors were HLA identical siblings. Conclusions. The usefulness of sHLA levels as the predictors of GVHR has to be interpreted with great caution, but they can be used as a part of the mosaic composed of the clinical image and other laboratory results indicating GVHR. The predictive value of sHLA in supernatants of MLC is still to be evaluated.
The human molecular genetics series
1st ed. 17, 438 s. : il.
- MeSH
- genetika člověka MeSH
- geny MHC třídy I MeSH
- geny MHC třídy II MeSH
- HLA-A antigeny MeSH
- imunita MeSH
- Publikační typ
- monografie MeSH
- Konspekt
- Obecná genetika. Obecná cytogenetika. Evoluce
- NLK Obory
- genetika, lékařská genetika
- biologie
Loss or downregulation of MHC class I molecules on tumour cells is a common mechanism by which tumours can escape from T-cell mediated immune responses. In this study we have investigated the immunologic crossreactivity between murine tumour cell lines expressing human papilloma virus (HPV) 16-derived E6/E7 oncoproteins with distinct surface expression of MHC class I molecules. The aims of this study were to demonstrate whether immune responses capable of coping with MHC class I-positive tumours can also be effective against their MHC class I-deficient derivatives and whether it is possible to induce immunity against MHC class I-deficient tumours by cellular vaccines based on MHC class I-deficient tumour cell lines. Our data showed that immunization with MHC class I-deficient but not with MHC class I positive tumour cells inhibited the growth of MHC class I-deficient tumours. In vivo depletion studies revealed that the mechanisms underlying effective immune responses against MHC class I-negative tumours in animals immunized with MHC class I-deficient tumour cells involved natural killer cells. The presented findings are of particular clinical relevance in the sense of construction of vaccines directed against a broad spectrum of HPV-associated tumours.
- MeSH
- financování organizované MeSH
- imunizace MeSH
- lidský papilomavirus 16 imunologie MeSH
- MHC antigeny I. třídy analýza imunologie MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádory imunologie terapie virologie MeSH
- proliferace buněk MeSH
- protinádorové vakcíny terapeutické užití MeSH
- zkřížené reakce MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
In the majority of human tumors, downregulation of major histocompatibility complex class I (MHC‑I) expression contributes to the escape from the host immune system and resistance to immunotherapy. Relevant animal models are therefore needed to enhance the efficacy of cancer immunotherapy. As loss of β‑2 microglobulin expression results in irreversible downregulation of surface MHC‑I molecules in various human tumors, the β‑2 microglobulin gene (B2m) was deactivated in a mouse oncogenic TC‑1 cell line and a TC‑1/dB2m cell line that was negative for surface MHC‑I expression was derived. Following stimulation with interferon γ, MHC‑I heavy chains, particularly the H‑2Db molecules, were found to be expressed at low levels on the cell surface, but without β‑2 microglobulin. B2m deactivation in TC‑1/dB2m cells led to reduced proliferation and tumor growth. These cells were insensitive to DNA vaccination and only weakly responsive to combined immunotherapy with a DNA vaccine and the ODN1826 adjuvant. In vivo depletion demonstrated that NK1.1+ cells were involved in both reduced tumor growth and an antitumor effect of immunotherapy. The number of immune cells infiltrating TC‑1/dB2m‑induced tumors was comparable with that in tumors developing from TC‑1/A9 cells characterized by reversible MHC‑I downregulation. However, the composition of the cell infiltrate was different and, most importantly, infiltration with immune cells was not increased in TC‑1/dB2m tumors after immunotherapy. Therefore, the TC‑1/dB2m cell line represents a clinically relevant tumor model that may be used for enhancement of cancer immunotherapy.
- MeSH
- beta-2-mikroglobulin genetika imunologie MeSH
- cytotoxické T-lymfocyty imunologie patologie MeSH
- imunoterapie MeSH
- interferon gama imunologie MeSH
- lidé MeSH
- MHC antigeny I. třídy genetika imunologie MeSH
- myši MeSH
- nádorové buněčné linie metabolismus MeSH
- nádory genetika imunologie patologie MeSH
- regulace genové exprese u nádorů genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
