Genome-wide Screens Identify Lineage- and Tumor-Specific Genes Modulating MHC-I- and MHC-II-Restricted Immunosurveillance of Human Lymphomas

Dersh, Devin; Phelan, James D.; Gumina, Megan E.; Wang, Boya; Arbuckle, Jesse H.; Hollý, Jaroslav; Kishton, Rigel J.; Markowitz, Tovah E.; Seedhom, Mina O.; Fridlyand, Nathan; Wright, George W.; Huang, Da Wei; Ceribelli, Michele; Thomas, Craig J.; Lack, Justin; Restifo, Nicholas P.; Kristie, Thomas M.; Staudt, Louis M.; Yewdell, Jonathan W.

doi:10.1016/j.immuni.2020.11.002

Cited by 99 publications

(71 citation statements)

References 91 publications

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“…The first notable feature of such a model is that these cells would remain MHC-I POS and therefore evade NK cell-mediated attack otherwise triggered by the loss of MHC-I inhibitory signals ( 34 ). Additionally, this model would suggest that attempts to epigenetically reactivate silent HLA-I alleles ( 44 ) may not lead to the restoration of tumor immunogenicity, since the most relevant neoantigen presentation may have already been lost via genetic inactivation of the corresponding presenting allele. A confirmation of these notions requires the combined analysis of the genetic HLA-I make-up and the neoantigen allele-specific load of the tumor vis à vis the T cell receptor specificities of autologous T cells.…”

Section: Discussionmentioning

confidence: 99%

Genetic mechanisms of HLA-I loss and immune escape in diffuse large B cell lymphoma

Fangazio

Ladewig

Gómez

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Fifty percent of diffuse large B cell lymphoma (DLBCL) cases lack cell-surface expression of the class I major histocompatibility complex (MHC-I), thus escaping recognition by cytotoxic T cells. Here we show that, across B cell lymphomas, loss of MHC-I, but not MHC-II, is preferentially restricted to DLBCL. To identify the involved mechanisms, we performed whole exome and targeted HLA deep-sequencing in 74 DLBCL samples, and found somatic inactivation of B2M and the HLA-I loci in 80% (34 of 42) of MHC-INEG tumors. Furthermore, 70% (22 of 32) of MHC-IPOS DLBCLs harbored monoallelic HLA-I genetic alterations (MHC-IPOS/mono), indicating allele-specific inactivation. MHC-INEG and MHC-IPOS/mono cases harbored significantly higher mutational burden and inferred neoantigen load, suggesting potential coselection of HLA-I loss and sustained neoantigen production. Notably, the analysis of >500,000 individuals across different cancer types revealed common germline HLA-I homozygosity, preferentially in DLBCL. In mice, germinal-center B cells lacking HLA-I expression did not progress to lymphoma and were counterselected in the context of oncogene-driven lymphomagenesis, suggesting that additional events are needed to license immune evasion. These results suggest a multistep process of HLA-I loss in DLBCL development including both germline and somatic events, and have direct implications for the pathogenesis and immunotherapeutic targeting of this disease.

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Section: Discussionmentioning

confidence: 99%

Genetic mechanisms of HLA-I loss and immune escape in diffuse large B cell lymphoma

Fangazio

Ladewig

Gómez

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…MHC-II expression is reduced in FL cells at both transcription and protein levels, resulting in impaired Ag presentation (Green et al, 2015;Andor et al, 2019). Pharmacologic inhibition of EZH2 or thymidylate synthase (TS) were found to enhance MHC-I expression in human DLBCL cell lines (Dersh et al, 2021). TS contributes to the biosynthesis of thymidine and is important for DNA replication and repair.…”

Section: Defective Antigen Presentationmentioning

confidence: 99%

“…TS contributes to the biosynthesis of thymidine and is important for DNA replication and repair. Interestingly, combined inhibition of EZH2 and TS displayed increased efficacy against DLBCL cells that are resistant to EZH2 inhibitors (Dersh et al, 2021).…”

Section: Defective Antigen Presentationmentioning

confidence: 99%

Epigenetic, Metabolic, and Immune Crosstalk in Germinal-Center-Derived B-Cell Lymphomas: Unveiling New Vulnerabilities for Rational Combination Therapies

Serganova

Chakraborty

Yamshon

et al. 2022

Front. Cell Dev. Biol.

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B-cell non-Hodgkin lymphomas (B-NHLs) are highly heterogenous by genetic, phenotypic, and clinical appearance. Next-generation sequencing technologies and multi-dimensional data analyses have further refined the way these diseases can be more precisely classified by specific genomic, epigenomic, and transcriptomic characteristics. The molecular and genetic heterogeneity of B-NHLs may contribute to the poor outcome of some of these diseases, suggesting that more personalized precision-medicine approaches are needed for improved therapeutic efficacy. The germinal center (GC) B-cell like diffuse large B-cell lymphomas (GCB-DLBCLs) and follicular lymphomas (FLs) share specific epigenetic programs. These diseases often remain difficult to treat and surprisingly do not respond advanced immunotherapies, despite arising in secondary lymphoid organs at sites of antigen recognition. Epigenetic dysregulation is a hallmark of GCB-DLBCLs and FLs, with gain-of-function (GOF) mutations in the histone methyltransferase EZH2, loss-of-function (LOF) mutations in histone acetyl transferases CREBBP and EP300, and the histone methyltransferase KMT2D representing the most prevalent genetic lesions driving these diseases. These mutations have the common effect to disrupt the interactions between lymphoma cells and the immune microenvironment, via decreased antigen presentation and responsiveness to IFN-γ and CD40 signaling pathways. This indicates that immune evasion is a key step in GC B-cell lymphomagenesis. EZH2 inhibitors are now approved for the treatment of FL and selective HDAC3 inhibitors counteracting the effects of CREBBP LOF mutations are under development. These treatments can help restore the immune control of GCB lymphomas, and may represent optimal candidate agents for more effective combination with immunotherapies. Here, we review recent progress in understanding the impact of mutant chromatin modifiers on immune evasion in GCB lymphomas. We provide new insights on how the epigenetic program of these diseases may be regulated at the level of metabolism, discussing the role of metabolic intermediates as cofactors of epigenetic enzymes. In addition, lymphoma metabolic adaptation can negatively influence the immune microenvironment, further contributing to the development of immune cold tumors, poorly infiltrated by effector immune cells. Based on these findings, we discuss relevant candidate epigenetic/metabolic/immune targets for rational combination therapies to investigate as more effective precision-medicine approaches for GCB lymphomas.

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“…Moreover, considering the high cellular and molecular heterogeneity in CNS tumors ( 81 ), we could also take into consideration the development of TCRs targeting multiple antigens to avoid the rapid subclone tumor selection due to the targeting of a single peptide. Regardless of these great features and versatility, the efficacy of TCR T-cells is strictly related to the HLA-peptide presentation, which is the major reason for treatment failure in those tumors characterized by HLA down-regulation ( 82 , 83 ). To overcome this issue, we have recently showed that IFN-γ treatment can re-establish HLA expression on brain tumor cells ( 72 ).…”

Section: Engineering T Cells To Improve Adoptive Cell Therapy In Cns Neoplasiamentioning

confidence: 99%

Innovative and Promising Strategies to Enhance Effectiveness of Immunotherapy for CNS Tumors: Where Are We?

et al. 2021

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Although there are several immunotherapy approaches for the treatment of Central Nervous System (CNS) tumors under evaluation, currently none of these approaches have received approval from the regulatory agencies. CNS tumors, especially glioblastomas, are tumors characterized by highly immunosuppressive tumor microenvironment, limiting the possibility of effectively eliciting an immune response. Moreover, the peculiar anatomic location of these tumors poses relevant challenges in terms of safety, since uncontrolled hyper inflammation could lead to cerebral edema and cranial hypertension. The most promising strategies of immunotherapy in neuro-oncology consist of the use of autologous T cells redirected against tumor cells through chimeric antigen receptor (CAR) constructs or genetically modified T-cell receptors. Trials based on native or genetically engineered oncolytic viruses and on vaccination with tumor-associated antigen peptides are also under evaluation. Despite some sporadic complete remissions achieved in clinical trials, the outcome of patients with CNS tumors treated with different immunotherapeutic approaches remains poor. Based on the lessons learned from these unsatisfactory experiences, novel immune-therapy approaches aimed at overcoming the profound immunosuppressive microenvironment of these diseases are bringing new hope to reach the cure for CNS tumors.

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Genome-wide Screens Identify Lineage- and Tumor-Specific Genes Modulating MHC-I- and MHC-II-Restricted Immunosurveillance of Human Lymphomas

Cited by 99 publications

References 91 publications

Genetic mechanisms of HLA-I loss and immune escape in diffuse large B cell lymphoma

Genetic mechanisms of HLA-I loss and immune escape in diffuse large B cell lymphoma

Epigenetic, Metabolic, and Immune Crosstalk in Germinal-Center-Derived B-Cell Lymphomas: Unveiling New Vulnerabilities for Rational Combination Therapies

Innovative and Promising Strategies to Enhance Effectiveness of Immunotherapy for CNS Tumors: Where Are We?

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