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Mass cytometry of Hodgkin lymphoma reveals a CD4⁺ regulatory T-cell-rich and exhausted T-effector microenvironment.

ABSTRACT: In classical Hodgkin lymphoma (cHL), the host antitumor immune response is ineffective. Hodgkin Reed-Sternberg (HRS) cells have multifaceted mechanisms to evade the immune system, including 9p24.1/CD274(PD-L1)/PDCD1LG2(PD-L2) genetic alterations, overexpression of PD-1 ligands, and associated T-cell exhaustion and additional structural bases of aberrant antigen presentation. The clinical success of PD-1 blockade in cHL suggests that the tumor microenvironment (TME) contains reversibly exhausted T effector cells (Teffs). However, durable responses are observed in patients with β2-microglobulin/major histocompatibility complex (MHC) class I loss on HRS cells, raising the possibility of non-CD8⁺ T cell-mediated mechanisms of efficacy of PD-1 blockade. These observations highlight the need for a detailed analysis of the cHL TME. Using a customized time-of-flight mass cytometry panel, we simultaneously assessed cell suspensions from diagnostic cHL biopsies and control reactive lymph node/tonsil (RLNT) samples. Precise phenotyping of immune cell subsets revealed salient differences between cHLs and RLNTs. The TME in cHL is CD4⁺ T-cell rich, with frequent loss of MHC class I expression on HRS cells. In cHLs, we found concomitant expansion of T helper 1 (Th1)-polarized Teffs and regulatory T cells (Tregs). The cHL Th1 Tregs expressed little or no PD-1, whereas the Th1 Teffs were PD-1⁺ The differential PD-1 expression and likely functional Th1-polarized CD4⁺ Tregs and exhausted Teffs may represent complementary mechanisms of immunosuppression in cHL.

SUBMITTER: Cader FZ

PROVIDER: S-EPMC6107878 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Mass cytometry of Hodgkin lymphoma reveals a CD4<sup>+</sup> regulatory T-cell-rich and exhausted T-effector microenvironment.

Cader Fathima Zumla FZ Schackmann Ron C J RCJ Hu Xihao X Wienand Kirsty K Redd Robert R Chapuy Bjoern B Ouyang Jing J Paul Nicole N Gjini Evisa E Lipschitz Mikel M Armand Philippe P Wu David D Fromm Jonathan R JR Neuberg Donna D Liu X Shirley XS Rodig Scott J SJ Shipp Margaret A MA

Blood 20180607 8

In classical Hodgkin lymphoma (cHL), the host antitumor immune response is ineffective. Hodgkin Reed-Sternberg (HRS) cells have multifaceted mechanisms to evade the immune system, including 9p24.1<i>/CD274(PD-L1)/PDCD1LG2(PD-L2)</i> genetic alterations, overexpression of PD-1 ligands, and associated T-cell exhaustion and additional structural bases of aberrant antigen presentation. The clinical success of PD-1 blockade in cHL suggests that the tumor microenvironment (TME) contains reversibly exh ...[more]

PMID: 29880615

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Project description:BackgroundCervical cancer (CC) is the fourth most common cancer in women worldwide. Although immunotherapy has been applied in clinical practice, its therapeutic efficacy remains far from satisfactory, necessitating further investigation of the mechanism of CC immune remodeling and exploration of novel treatment targets. This study aimed to investigate the mechanism of CC immune remodeling and explore potential therapeutic targets.MethodsWe conducted single-cell RNA sequencing on a total of 17 clinical specimens, including normal cervical tissues, high-grade squamous intraepithelial lesions, and CC tissues. To validate our findings, we conducted multicolor immunohistochemical staining of CC tissues and constructed a subcutaneous tumorigenesis model in C57BL/6 mice using murine CC cell lines (TC1) to evaluate the effectiveness of combination therapy involving indoleamine 2,3-dioxygenase 1 (IDO1) inhibition and immune checkpoint blockade (ICB). We used the unpaired two-tailed Student's t-test, Mann-Whitney test, or Kruskal-Wallis test to compare continuous data between two groups and one-way ANOVA with Tukey's post hoc test to compare data between multiple groups.ResultsMalignant cervical epithelial cells did not manifest noticeable signs of tumor escape, whereas lysosomal-associated membrane protein 3-positive (LAMP3+ ) dendritic cells (DCs) in a mature state with immunoregulatory roles were found to express IDO1 and affect tryptophan metabolism. These cells interacted with both tumor-reactive exhausted CD8+ T cells and CD4+ regulatory T cells, synergistically forming a vicious immunosuppressive cycle and mediating CC immune escape. Further validation through multicolor immunohistochemical staining showed co-localization of neoantigen-reactive T cells (CD3+ , CD4+ /CD8+ , and PD-1+ ) and LAMP3+ DCs (CD80+ and PD-L1+ ). Additionally, a combination of the IDO1 inhibitor with an ICB agent significantly reduced tumor volume in the mouse model of CC compared with an ICB agent alone.ConclusionsOur study suggested that a combination treatment consisting of targeting IDO1 and ICB agent could improve the therapeutic efficacy of current CC immunotherapies. Additionally, our results provided crucial insights for designing drugs and conducting future clinical trials for CC.

Dataset Information

Mass cytometry of Hodgkin lymphoma reveals a CD4⁺ regulatory T-cell-rich and exhausted T-effector microenvironment.

Publications

Mass cytometry of Hodgkin lymphoma reveals a CD4<sup>+</sup> regulatory T-cell-rich and exhausted T-effector microenvironment.

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Mass cytometry of Hodgkin lymphoma reveals a CD4+ regulatory T-cell-rich and exhausted T-effector microenvironment.

Publications

Mass cytometry of Hodgkin lymphoma reveals a CD4<sup>+</sup> regulatory T-cell-rich and exhausted T-effector microenvironment.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Mass cytometry of Hodgkin lymphoma reveals a CD4⁺ regulatory T-cell-rich and exhausted T-effector microenvironment.