The regulatory network behind MHC class I expression

Jongsma, Marlieke L.M.; Guarda, Greta; Spaapen, Robbert M.

doi:10.1016/j.molimm.2017.12.005

Cited by 130 publications

(115 citation statements)

References 87 publications

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“…Previous studies showed that EZH2 mutations may mediate MHC-II expression through downregulation of CIITA, which is the master regulator of MHC-II genes (35). In addition, NLRC5 has been recently identified as a transactivator of MHC class I, which was shown to regulate MHC-I expression by reducing H3K27me3 on the MHC-I promoter (10,36). As shown in several previous publications, the expression levels of NLRC5 and MHC-I are highly correlated, with more NLRC5 resulting in higher MHC-I expression and increased MHC-I cell surface levels (10,37).…”

Section: Discussionmentioning

confidence: 99%

Molecular and Genetic Characterization of MHC Deficiency Identifies EZH2 as Therapeutic Target for Enhancing Immune Recognition

et al. 2019

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We performed a genomic, transcriptomic, and immunophenotypic study of 347 patients with diffuse large B-cell lymphoma (DLBCL) to uncover the molecular basis underlying acquired defi ciency of MHC expression. Low MHC-II expression defi nes tumors originating from the centroblast-rich dark zone of the germinal center (GC) that was associated with inferior prognosis. MHC-II-defi cient tumors were characterized by somatically acquired gene mutations reducing MHC-II expression and a lower amount of tumor-infi ltrating lymphocytes. In particular, we demonstrated a strong enrichment of EZH2 mutations in both MHC-I-and MHC-II-negative primary lymphomas, and observed reduced MHC expression and T-cell infi ltrates in murine lymphoma models expressing mutant Ezh2 Y641. Of clinical relevance, EZH2 inhibitors signifi cantly restored MHC expression in EZH2-mutated human DLBCL cell lines. Hence, our fi ndings suggest a tumor progression model of acquired immune escape in GC-derived lymphomas and pave the way for development of complementary therapeutic approaches combining immunotherapy with epigenetic reprogramming. SIGNIFICANCE: We demonstrate how MHC-defi cient lymphoid tumors evolve in a cell-of-origin-specifi c context. Specifi cally, EZH2 mutations were identifi ed as a genetic mechanism underlying acquired MHC defi ciency. The paradigmatic restoration of MHC expression by EZH2 inhibitors provides the rationale for synergistic therapies combining immunotherapies with epigenetic reprogramming to enhance tumor recognition and elimination.

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Section: Discussionmentioning

confidence: 99%

Molecular and Genetic Characterization of MHC Deficiency Identifies EZH2 as Therapeutic Target for Enhancing Immune Recognition

et al. 2019

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“…The cAMP-responsive element binding protein 1 (CREB1) and the activating transcription factor 1 (ATF1) bind the X2 box; the nuclear transcription factor Y (NFY) complex interacts with the Y box. Instead, the elements interacting with W/S box remains poorly defined [ 106 , 107 ]. The interactors with SXY module of genes belonging to both HLA class I and II are crucial elements in the transcriptional control.…”

Section: Human Leucocyte Antigen and Antigen Presentation Machinermentioning

confidence: 99%

“…The administration of IFNs might effectively counteract HLA class I down-regulation in cancer cells by boosting the presentation of tumor specific-associated antigens [ 254 , 255 , 256 , 257 ]. A phase 0 clinical trial showed that systemic administration of IFN-γ increases not only HLA class I expression on tumor cells, but also T-cell infiltration in cold tumors [ 258 ] IFN-mediated up-regulation of HLA class I derived peptide complexes occurs via activation of the Jak/STAT pathway which induces the binding of IRFs to ISRE motifs located in HLA class I promoter region [ 107 , 254 ]. In addition, IFN-γ-mediated HLA class I derived peptide complex up-regulation is also associated to an increased histone demethylation and acetylation of APM genes in the MHC locus, particularly of histone H3 in TAP1 promoter locus [ 259 ].…”

Section: Restoring Hla Class I Expression As a Novel Therapeutic Smentioning

confidence: 99%

Role of Human Leukocyte Antigen System as A Predictive Biomarker for Checkpoint-Based Immunotherapy in Cancer Patients

Sabbatino

Liguori

Polcaro

et al. 2020

IJMS

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Recent advances in cancer immunotherapy have clearly shown that checkpoint-based immunotherapy is effective in a small subgroup of cancer patients. However, no effective predictive biomarker has been identified so far. The major histocompatibility complex, better known in humans as human leukocyte antigen (HLA), is a very polymorphic gene complex consisting of more than 200 genes. It has a crucial role in activating an appropriate host immune response against pathogens and tumor cells by discriminating self and non-self peptides. Several lines of evidence have shown that down-regulation of expression of HLA class I antigen derived peptide complexes by cancer cells is a mechanism of tumor immune escape and is often associated to poor prognosis in cancer patients. In addition, it has also been shown that HLA class I and II antigen expression, as well as defects in the antigen processing machinery complex, may predict tumor responses in cancer immunotherapy. Nevertheless, the role of HLA in predicting tumor responses to checkpoint-based immunotherapy is still debated. In this review, firstly, we will describe the structure and function of the HLA system. Secondly, we will summarize the HLA defects and their clinical significance in cancer patients. Thirdly, we will review the potential role of the HLA as a predictive biomarker for checkpoint-based immunotherapy in cancer patients. Lastly, we will discuss the potential strategies that may restore HLA function to implement novel therapeutic strategies in cancer patients.

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“…Nevertheless, reduction of MHC-I expression is a reversible state. Type I and type II interferon signaling contribute to the upregulation of MHC-I on tumor cells [28,[48][49][50]. In our previous studies [9] we showed that replicating arenaviruses induce a strong interferon response via the activation of the innate immune response.…”

Section: Furthermore Replicating Non-oncolytic Arenaviruses Like Lcmmentioning

confidence: 96%

Viral infection overcomes ineffectiveness of anti-tumoral CD8+ T cell mediated cytotoxicity

Zhou

Kardash

Bhat

et al. 2019

Preprint

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With the integration of PD-1 and CTLA-4 targeting immune checkpoint blockade into cancer treatment regimes, the anti-tumoral cytotoxicity of tumor-specific CD8 + T cells is well established.However, while the unresponsiveness of CD8 + T cells against big tumors is mainly explained by T cell exhaustion, other factors contributing to CD8 + T cell failure remain not well studied. Here we used a mouse melanoma model to study the interaction of growing tumor cells, innate immunity and CD8 + T cell responses induced by viral replication. Mouse model of melanoma (B16F10-OVA) and infections with arenaviruses. Growing B16F10-OVA cells did not induce systemic ablation of tumor specific CD8 + T cells. However, despite the presence of tumor-infiltrating CD8 + T cells, the anti-tumoral immune response was very limited. T cell anergy against the tumor was accompanied with a strong down-regulation of MHC-I on advanced tumors. LCMV infection restored the MHC class I expression, enhanced T cell function and lead to tumor regression. This study shows that tumor progression does not necessary lead to systemic exhaustion of the anti-tumoral CD8 + T cell response. Lack of innate signals is an additional reason for limited CD8 + T cell mediated cytotoxicity against the tumor.

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The regulatory network behind MHC class I expression

Cited by 130 publications

References 87 publications

Molecular and Genetic Characterization of MHC Deficiency Identifies EZH2 as Therapeutic Target for Enhancing Immune Recognition

Molecular and Genetic Characterization of MHC Deficiency Identifies EZH2 as Therapeutic Target for Enhancing Immune Recognition

Role of Human Leukocyte Antigen System as A Predictive Biomarker for Checkpoint-Based Immunotherapy in Cancer Patients

Viral infection overcomes ineffectiveness of anti-tumoral CD8+ T cell mediated cytotoxicity

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