Single Cell Transcriptome Analysis Reveals Disease-Defining T Cell Subsets in the Tumor Microenvironment of Classic Hodgkin Lymphoma

Aoki, Tomohiro; Chong, Lauren C.; Takata, Katsuyoshi; Milne, Katy; Hav, Monirath; Colombo, Anthony; Chavez, Elizabeth A.; Miyata‐Takata, Tomoko; Lam, Vivian; Ghesquiere, Chanel; Kos, Daniel; Goodyear, Talia; Zhang, Allen W.; Wang, Xuehai; Saberi, Saeed; Ding, Jiarui; Farinha, Pedro; Weng, Andrew P.; Savage, Kerry J.; Scott, David W.; Krystal, Gerald; Nelson, Brad H.; Mottok, Anja; Merchant, Akil; Shah, Sohrab P.

doi:10.1182/blood-2019-121584

Cited by 33 publications

(62 citation statements)

References 35 publications

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“…The TME of cHL possesses various innate immune cells such as macrophages and dendritic cells. 32,55 These cells also possess MHC-II expression and act as antigen-presenting cells, which may be involved in antitumor immunity. In addition, HRS cells have complementary mechanisms of immune evasion including alterations of NF-kB, JAK/STAT, PI3K signals, PD-L1, and B2M, all of which are crucial for immune responses.…”

Section: Discussionmentioning

confidence: 99%

The critical role of CD4+ T cells in PD-1 blockade against MHC-II–expressing tumors such as classic Hodgkin lymphoma

Nagasaki

Togashi

Sugawara³

et al. 2020

Blood Advances

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Classic Hodgkin lymphoma (cHL) responds markedly to PD-1 blockade therapy, and the clinical responses are reportedly dependent on expression of major histocompatibility complex class II (MHC-II). This dependence is different from other solid tumors, in which the MHC class I (MHC-I)/CD8+ T-cell axis plays a critical role. In this study, we investigated the role of the MHC-II/CD4+ T-cell axis in the antitumor effect of PD-1 blockade on cHL. In cHL, MHC-I expression was frequently lost, but MHC-II expression was maintained. CD4+ T cells highly infiltrated the tumor microenvironment of MHC-II–expressing cHL, regardless of MHC-I expression status. Consequently, CD4+ T-cell, but not CD8+ T-cell, infiltration was a good prognostic factor in cHL, and PD-1 blockade showed antitumor efficacy against MHC-II–expressing cHL associated with CD4+ T-cell infiltration. Murine lymphoma and solid tumor models revealed the critical role of antitumor effects mediated by CD4+ T cells: an anti-PD-1 monoclonal antibody exerted antitumor effects on MHC-I−MHC-II+ tumors but not on MHC-I−MHC-II− tumors, in a cytotoxic CD4+ T-cell–dependent manner. Furthermore, LAG-3, which reportedly binds to MHC-II, was highly expressed by tumor-infiltrating CD4+ T cells in MHC-II–expressing tumors. Therefore, the combination of LAG-3 blockade with PD-1 blockade showed a far stronger antitumor immunity compared with either treatment alone. We propose that PD-1 blockade therapies have antitumor effects on MHC-II–expressing tumors such as cHL that are mediated by cytotoxic CD4+ T cells and that LAG-3 could be a candidate for combination therapy with PD-1 blockade.

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Section: Discussionmentioning

confidence: 99%

The critical role of CD4+ T cells in PD-1 blockade against MHC-II–expressing tumors such as classic Hodgkin lymphoma

Nagasaki

Togashi

Sugawara³

et al. 2020

Blood Advances

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“…Currently, the randomized phase 2 study of brentuximab vedotin and nivolumab with or without ipilimumab is ongoing (NCT01896999) to assess the efficacy of dual CTLA-4 and PD-1 blockade. LAG-3 might be a potential target considering the recent single-cell RNA sequence (scRNA-seq) analysis which showed that a subset of HL-associated T cells expressed high levels of this checkpoint molecule [ 74 ]. Alternatively, given that loss of MHC-II confers therapeutic resistance to HL, harnessing innate immunity might be a key approach.…”

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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“…In the study, increased LAG3 + T cells were shown to be in the direct vicinity of MHC class-II-deficient tumor cells. 73 Zhu et al investigated ovarian cancer patients using IMC to identify biomarkers of immunotherapy response. In the study, the authors found that the highest increase in CD8 + T cells and forkhead box protein P3 (FoxP3) + cells was found in patients responding to the combination of durvalumab and tremelimumab.…”

Section: Imaging Mass Cytometrymentioning

confidence: 99%

The evolving landscape of predictive biomarkers in immuno‐oncology with a focus on spatial technologies

et al. 2020

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Immunotherapies have shown long‐lasting and unparalleled responses for cancer patients compared to conventional therapy. However, they seem to only be effective in a subset of patients. Therefore, it has become evident that a greater understanding of the tumor microenvironment (TME) is required to understand the nuances which may be at play for a favorable outcome to therapy. The immune contexture of the TME is an important factor in dictating how well a tumor may respond to immune checkpoint inhibitors. While traditional immunohistochemistry techniques allow for the profiling of cells in the tumor, this is often lost when tumors are analysed using bulk tissue genomic approaches. Moreover, the actual cellular proportions, cellular heterogeneity and deeper spatial distribution are lacking in characterisation. Advances in tissue interrogation technologies have given rise to spatially resolved characterisation of the TME. This review aims to provide an overview of the current methodologies that are used to profile the TME, which may provide insights into the immunopathology associated with a favorable outcome to immunotherapy.

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Single Cell Transcriptome Analysis Reveals Disease-Defining T Cell Subsets in the Tumor Microenvironment of Classic Hodgkin Lymphoma

Cited by 33 publications

References 35 publications

The critical role of CD4+ T cells in PD-1 blockade against MHC-II–expressing tumors such as classic Hodgkin lymphoma

The critical role of CD4+ T cells in PD-1 blockade against MHC-II–expressing tumors such as classic Hodgkin lymphoma

Targeting immune checkpoints in hematological malignancies

The evolving landscape of predictive biomarkers in immuno‐oncology with a focus on spatial technologies

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