The microenvironmental niche in classic Hodgkin lymphoma is enriched for CTLA-4- positive T-cells that are PD-1-negative

Patel, Sanjay; Weirather, Jason L.; Lipschitz, Mikel; Lako, Ana; Chen, Pei-Hsuan; Griffin, Gabriel K.; Armand, Philippe; Shipp, Margaret A.; Rodig, Scott J.

doi:10.1182/blood.2019002206

Cited by 89 publications

(111 citation statements)

References 38 publications

(52 reference statements)

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“…functional insight, the presented work is highly complementary to recently published studies interrogating malignant celltumor microenvironment interactions using single-cell technologies, including multicolor immunohistochemistry,8 flowbased mass cytometry,9 imaging mass cytometry, single-cell RNAseq, 10 and, as Rosette formation and T-cell activation in HL. The schematic highlights the immune synapse between a malignant Reed-Sternberg cell and a CD4 1 T cell.…”

mentioning

confidence: 71%

“…However, IVIGs usually have only a temporary action, and as in other MGCS (Schnitzler syndrome being the exception because of the impressive efficacy of anti-IL-1 antibodies), a secondary treatment, which targets the B-cell clone producing the toxic MIg, is often necessary. 5,8 CANOMAD/ CANDA is associated with a monoclonal IgM, and the use of rituximab alone or associated with other agents is logical, assuming that the B-cell clone expresses CD20, even if, as in other MGCS, the nature of the responsible clone must, whenever possible, be precisely characterized. Le Cann et al proposed a functional algorithm with first IVIG and then a rituximab-based regimen for nonresponding or early relapsing patients.…”

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confidence: 99%

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Architecture and interior design of Hodgkin lymphoma

Steidl

2020

Blood

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confidence: 71%

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confidence: 99%

Architecture and interior design of Hodgkin lymphoma

Steidl

2020

Blood

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“…Indeed, Roemer et al also reported that β2-microglobulin (β2M) and MHC-I were not expressed on tumor cells in more than 60% of HL patients and that the expression level of MHC-II and PD-L1 predicts therapeutic response to nivolumab in HL patients [ 72 ]. More recently, Patel et al investigated checkpoint molecules by multiplexed immunofluorescence imaging and observed the expansion of CTLA-4 + PD-1 − CD4 T cells in close proximity to CD86 + tumor cells or tumor-associated macrophages (TAMs) [ 73 ]. This suggests that the interaction between CTLA-4 and CD86 might also act as a key negative regulator in HL.…”

Section: Clinical Response and Resistance To Immune Checkpoint Blockamentioning

confidence: 99%

Targeting immune checkpoints in hematological malignancies

2020

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Immune checkpoint blockade (ICB) therapies such as anti-programmed death 1 (PD-1) and anti-CTLA-4 (cytotoxic T lymphocyte-associated protein 4) have dramatically transformed treatment in solid tumor oncology. While immunotherapeutic approaches such as stem cell transplantation and anti-cancer monoclonal antibodies have made critical contributions to improve outcomes in hematological malignancies, clinical benefits of ICB are observed in only limited tumor types that are particularly characterized by a high infiltration of immune cells. Importantly, even patients that initially respond to ICB are unable to achieve long-term disease control using these therapies. Indeed, primary and acquired resistance mechanisms are differentially orchestrated in hematological malignancies depending on tumor types and/or genotypes, and thus, an in-depth understanding of the disease-specific immune microenvironments will be essential in improving efficacy. In addition to PD-1 and CTLA-4, various T cell immune checkpoint molecules have been characterized that regulate T cell responses in a non-redundant manner. Several lines of evidence suggest that these T cell checkpoint molecules might play unique roles in hematological malignancies, highlighting their potential as therapeutic targets. Targeting innate checkpoint molecules on natural killer cells and/or macrophages has also emerged as a rational approach against tumors that are resistant to T cell-mediated immunity. Given that various monoclonal antibodies against tumor surface proteins have been clinically approved in hematological malignancies, innate checkpoint blockade might play a key role to augment antibody-mediated cellular cytotoxicity and phagocytosis. In this review, we discuss recent advances and emerging roles of immune checkpoint blockade in hematological malignancies.

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“…CTLA4 is expressed more broadly than LAG3 on T cells populating the cHL microenvironment [ 54 ]. Patel and colleagues have recently found that CTLA4 + T cells, usually staining negative for Foxp3, outnumbered PD-1 + and LAG3 + cells in cHL.…”

Section: The Spectrum Of T-helper Subsets In the Chl Microenvironmmentioning

confidence: 99%

The Evolving Knowledge on T and NK Cells in Classic Hodgkin Lymphoma: Insights into Novel Subsets Populating the Immune Microenvironment

Ferrarini

Rigo

Visco

et al. 2020

Cancers

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Classic Hodgkin lymphoma (cHL) is a unique lymphoid neoplasm characterized by extensive immune infiltrates surrounding rare malignant Hodgkin Reed–Sternberg (HRS) cells. Different subsets of T and NK cells have long been recognized in the cHL microenvironment, yet their distinct contribution to disease pathogenesis has remained enigmatic. Very recently, novel platforms for high dimensional analysis of immune cells, such as single-cell RNA sequencing and mass cytometry, have revealed unanticipated insights into the composition of T- and NK-cell compartments in cHL. Advances in imaging techniques have better defined specific T-helper subpopulations physically interacting with neoplastic cells. In addition, the identification of novel cytotoxic subsets with an exhausted phenotype, typically enriched in cHL milieu, is shedding light on previously unrecognized immune evasion mechanisms. This review examines the immunological features and the functional properties of T and NK subsets recently identified in the cHL microenvironment, highlighting their pathological interplay with HRS cells. We also discuss how this knowledge can be exploited to predict response to immunotherapy and to design novel strategies to improve PD-1 blockade efficacy.

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The microenvironmental niche in classic Hodgkin lymphoma is enriched for CTLA-4- positive T-cells that are PD-1-negative

Abstract: Key Points CTLA-4 is enriched in the microenvironmental niche in cHL, and identifies a T-cell population largely distinct from PD-1 CD86, the natural ligand for CTLA-4, is enriched in the niche and expressed on HRS cells and a subset of TAMs that also express PD-L1

Cited by 89 publications

References 38 publications

Architecture and interior design of Hodgkin lymphoma

Architecture and interior design of Hodgkin lymphoma

Targeting immune checkpoints in hematological malignancies

The Evolving Knowledge on T and NK Cells in Classic Hodgkin Lymphoma: Insights into Novel Subsets Populating the Immune Microenvironment

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