HLA class I is most tightly linked to levels of tapasin compared with other antigen-processing proteins in glioblastoma

Thuring, Camilla; Follin, Elna; Geironson, Linda; Freyhult, Eva; Junghans, Victoria; Harndahl, Mikkel; Buus, Søren; Paulsson, Kajsa

doi:10.1038/bjc.2015.297

Cited by 19 publications

(14 citation statements)

References 52 publications

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“…Factors limiting the efficacy of T cell-based therapeutic strategies include the low mutational burden of GBM, the limited trafficking of immune cells within the tumor and the highly suppressive nature of the tumor microenvironment (TME) ( Desai et al, 2019 ). Another important mechanism that plays a role in the limited clinical impact of T cell-based immunotherapies is represented by defects in HLA class I and APM component expression and function in GBM ( Facoetti et al, 2005 ; Thuring et al, 2015 ). Downregulation, loss or lack of function of HLA class-I APM components have a negative impact on T cell-mediated recognition and lysis of GBM cells.…”

Section: Immunotherapy Based Strategies For the Treatment Of Gbmmentioning

confidence: 99%

CAR T Cell-Based Immunotherapy for the Treatment of Glioblastoma

et al. 2021

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Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary brain tumor in adults. Current treatment options typically consist of surgery followed by chemotherapy or more frequently radiotherapy, however, median patient survival remains at just over 1 year. Therefore, the need for novel curative therapies for GBM is vital. Characterization of GBM cells has contributed to identify several molecules as targets for immunotherapy-based treatments such as EGFR/EGFRvIII, IL13Rα2, B7-H3, and CSPG4. Cytotoxic T lymphocytes collected from a patient can be genetically modified to express a chimeric antigen receptor (CAR) specific for an identified tumor antigen (TA). These CAR T cells can then be re-administered to the patient to identify and eliminate cancer cells. The impressive clinical responses to TA-specific CAR T cell-based therapies in patients with hematological malignancies have generated a lot of interest in the application of this strategy with solid tumors including GBM. Several clinical trials are evaluating TA-specific CAR T cells to treat GBM. Unfortunately, the efficacy of CAR T cells against solid tumors has been limited due to several factors. These include the immunosuppressive tumor microenvironment, inadequate trafficking and infiltration of CAR T cells and their lack of persistence and activity. In particular, GBM has specific limitations to overcome including acquired resistance to therapy, limited diffusion across the blood brain barrier and risks of central nervous system toxicity. Here we review current CAR T cell-based approaches for the treatment of GBM and summarize the mechanisms being explored in pre-clinical, as well as clinical studies to improve their anti-tumor activity.

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Section: Immunotherapy Based Strategies For the Treatment Of Gbmmentioning

confidence: 99%

CAR T Cell-Based Immunotherapy for the Treatment of Glioblastoma

et al. 2021

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“…12,13,[19][20][21] It is also reported that loss of tapasin is more frequent among the other antigen-processing machinery (APM) components, strongly suggesting its central role in escape from CTL immune surveillance to tumors. 15,22 Impaired CTL responses against tapasin-deficient cells have been well established in mouse models. 8,9 In human cases, loss of tapasin alters the peptide repertoire presented by HLA-B Ã 2705 and results in a decrease in alloreactive CTL responses.…”

Section: Introductionmentioning

confidence: 99%

Loss of tapasin in human lung and colon cancer cells and escape from tumor-associated antigen-specific CTL recognition

et al. 2017

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Cytotoxic T-lymphocytes (CTLs) lyse target cells after recognizing the complexes of peptides and MHC class I molecules (pMHC I) on cell surfaces. Tapasin is an essential component of the peptide-loading complex (PLC) and its absence influences the surface repertoire of MHC class I peptides. In the present study, we assessed tapasin expression in 85 primary tumor lesions of non-small cell lung cancer (NSCLC) patients, demonstrating that tapasin expression positively correlated with patient survival. CD8C T-cell infiltration of tumor lesions was synergistically observed with tapasin expression and correlated positively with survival. To establish a direct link between loss of tapasin and CTL recognition in human cancer models, we targeted the tapasin gene by CRISPR/Cas9 system and generated tapasin-deficient variants of human lung as well as colon cancer cells. We induced the CTLs recognizing endogenous tumor-associated antigens (TAA), survivin or cep55, and they responded to each tapasin-proficient wild type. In contrast, both CTL lines ignored the tapasin-deficient variants despite their antigen expression. Moreover, the adoptive transfer of the cep55-specific CTL line failed to prevent tumor growth in mice bearing the tapasindeficient variant. Loss of tapasin most likely limited antigen processing of TAAs and led to escape from TAA-specific CTL recognition. Tapasin expression is thus a key for CTL surveillance against human cancers.

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“…Thus, some MHC I allotypes like the human leukocyte antigen (HLA) B*44:05 ( 16 ) and the chicken BF2*15:01 molecules ( 19 , 20 ) are relatively efficient at selecting high-affinity peptide cargo in the absence of tapasin. This can be advantageous because the expression of tapasin can be down-regulated, as has been documented with a variety of tumors and which is generally associated with worse prognosis ( 21 – 24 ) or targeted by pathogen-encoded immune evasion molecules ( 25 , 26 ). Conversely, other allotypes, like HLA-B*44:02 and BF2*19:01, are inefficient at loading peptide cargo in the absence of tapasin.…”

Section: Introductionmentioning

confidence: 99%

Direct evidence for conformational dynamics in major histocompatibility complex class I molecules

Hateren¹,

Anderson

Bailey³

et al. 2017

Journal of Biological Chemistry

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Major histocompatibility complex class I molecules (MHC I) help protect jawed vertebrates by binding and presenting immunogenic peptides to cytotoxic T lymphocytes. Peptides are selected from a large diversity present in the endoplasmic reticulum. However, only a limited number of peptides complement the polymorphic MHC specificity determining pockets in a way that leads to high-affinity peptide binding and efficient antigen presentation. MHC I molecules possess an intrinsic ability to discriminate between peptides, which varies in efficiency between allotypes, but the mechanism of selection is unknown. Elucidation of the selection mechanism is likely to benefit future immune-modulatory therapies. Evidence suggests peptide selection involves transient adoption of alternative, presumably higher energy conformations than native peptide–MHC complexes. However, the instability of peptide-receptive MHC molecules has hindered characterization of such conformational plasticity. To investigate the dynamic nature of MHC, we refolded MHC proteins with peptides that can be hydrolyzed by UV light and thus released. We compared the resultant peptide-receptive MHC molecules with non-hydrolyzed peptide-loaded MHC complexes by monitoring the exchange of hydrogen for deuterium in solution. We found differences in hydrogen–deuterium exchange between peptide-loaded and peptide-receptive molecules that were negated by the addition of peptide to peptide-receptive MHC molecules. Peptide hydrolysis caused significant increases in hydrogen–deuterium exchange in sub-regions of the peptide-binding domain and smaller increases elsewhere, including in the α3 domain and the non-covalently associated β2-microglobulin molecule, demonstrating long-range dynamic communication. Comparing two MHC allotypes revealed allotype-specific differences in hydrogen–deuterium exchange, consistent with the notion that MHC I plasticity underpins peptide selection.

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HLA class I is most tightly linked to levels of tapasin compared with other antigen-processing proteins in glioblastoma

Cited by 19 publications

References 52 publications

CAR T Cell-Based Immunotherapy for the Treatment of Glioblastoma

CAR T Cell-Based Immunotherapy for the Treatment of Glioblastoma

Loss of tapasin in human lung and colon cancer cells and escape from tumor-associated antigen-specific CTL recognition

Direct evidence for conformational dynamics in major histocompatibility complex class I molecules

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