Single-cell transcriptome profiling reveals intra-tumoral heterogeneity in human chordomas

Duan, Wanru; Zhang, Boyan; Li, Xin-Qiang; Chen, Wei; Jia, Shanhang; Zong, Xin; Jian, Qiang; Jian, Fengzeng; Chou, Dean; Chen, Zan

doi:10.1007/s00262-022-03152-1

Cited by 24 publications

(30 citation statements)

References 56 publications

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“…In literature, descriptions of immune phenotypes in chordoma are mainly based on H&E staining and immunohistochemistry, which provides limited insight. 36–39 Surprisingly, single-cell RNA-sequencing and multiplex IF techniques were applied in studies of the chordoma TIME only since last year, 40 41 with their findings supporting the current results, as macrophages were reported to significantly infiltrate the chordoma parenchyma, while T cells exhibited stromal infiltration. 41 To our knowledge, this is the first report of spectral flow cytometry analysis in chordoma, also in combination with mIF for TIME characterization.…”

Section: Discussionsupporting

confidence: 84%

Chordoma recruits and polarizes tumor-associated macrophages via secreting CCL5 to promote malignant progression

Shi

Lou

et al. 2023

J Immunother Cancer

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BackgroundChordoma is an extremely rare, locally aggressive malignant bone tumor originating from undifferentiated embryonic remnants. There are no effective therapeutic strategies for chordoma. Herein, we aimed to explore cellular interactions within the chordoma immune microenvironment and provide new therapeutic targets.MethodsSpectrum flow cytometry and multiplex immunofluorescence (IF) staining were used to investigate the immune microenvironment of chordoma. Cell Counting Kit-8, Edu, clone formation, Transwell, and healing assays were used to validate tumor functions. Flow cytometry and Transwell assays were used to analyze macrophage phenotype and chemotaxis alterations. Immunohistochemistry, IF, western blot, PCR, and ELISA assays were used to analyze molecular expression. An organoid model and a xenograft mouse model were constructed to investigate the efficacy of maraviroc (MVC).ResultsThe chordoma immune microenvironment landscape was characterized, and we observed that chordoma exhibits a typical immune exclusion phenotype. However, macrophages infiltrating the tumor zone were also noted. Through functional assays, we demonstrated that chordoma-secreted CCL5 significantly promoted malignancy progression, macrophage recruitment, and M2 polarization. In turn, M2 macrophages markedly enhanced the proliferation, invasion, and migration viability of chordoma. CCL5 knockdown and MVC (CCL5/CCR5 inhibitor) treatment both significantly inhibited chordoma malignant progression and M2 macrophage polarization. We established chordoma patient-derived organoids, wherein MVC exhibited antitumor effects, especially in patient 4, with robust killing effect. MVC inhibits chordoma growth and lung metastasis in vivo.ConclusionsOur study implicates that the CCL5–CCR5 axis plays an important role in the malignant progression of chordoma and the regulation of macrophages, and that the CCL5–CCR5 axis is a potential therapeutic target in chordoma.

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Section: Discussionsupporting

confidence: 84%

Chordoma recruits and polarizes tumor-associated macrophages via secreting CCL5 to promote malignant progression

Shi

Lou

et al. 2023

J Immunother Cancer

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“…Similarly, uniform analysis methods applied via HALO allow for high throughput, precise, and comparable results amongst assorted chordoma samples. Although chordomas are known to be heterogeneous with varying levels of expression of the markers we examined (7), a large sample size aided in achieving a more comprehensive idea of the chordoma TIME than what has previously been described, with the inclusion of myeloid and NK cell compartments.…”

Section: Discussionmentioning

confidence: 99%

“…The study of the tumor microenvironment, consisting of tumor, immune, vascular, and fibroblast cells (7), has garnered increased recent attention due to advances in immunotherapeutic options. An understanding of the host immune antitumor response can be important in prognostication, tumor phenotyping, and optimization of targeted treatment (8).…”

Section: Introductionmentioning

confidence: 99%

“…An understanding of the host immune antitumor response can be important in prognostication, tumor phenotyping, and optimization of targeted treatment (8). However, the characterization of chordoma's complex and heterogeneous tumor immune microenvironment continues to be preliminary (7,9). Of particular interest in the TIME are the myeloid, T cell, and natural killer cell compartments (10-12).…”

Section: Introductionmentioning

confidence: 99%

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Multi-spectral immunofluorescence evaluation of the myeloid, T cell, and natural killer cell tumor immune microenvironment in chordoma may guide immunotherapeutic strategies

Lopez

Robbins²,

Kowalczyk³

et al. 2022

Front. Oncol.

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BackgroundChordoma is a rare, invasive, and devastating bone malignancy of residual notochord tissue that arises at the skull base, sacrum, or spine. In order to maximize immunotherapeutic approaches as a potential treatment strategy in chordoma it is important to fully characterize the tumor immune microenvironment (TIME). Multispectral immunofluorescence (MIF) allows for comprehensive evaluation of tumor compartments, molecular co-expression, and immune cell spatial relationships. Here we implement MIF to define the myeloid, T cell, and natural killer (NK) cell compartments in an effort to guide rational design of immunotherapeutic strategies for chordoma.MethodsChordoma tumor tissue from 57 patients was evaluated using MIF. Three panels were validated to assess myeloid cell, T cell, and NK cell populations. Slides were stained using an automated system and HALO software objective analysis was utilized for quantitative immune cell density and spatial comparisons between tumor and stroma compartments.ResultsChordoma TIME analysis revealed macrophage infiltration of the tumor parenchyma at a significantly higher density than stroma. In contrast, helper T cells, cytotoxic T cells, and T regulatory cells were significantly more abundant in stroma versus tumor. T cell compartment infiltration more commonly demonstrated a tumor parenchymal exclusion pattern, most markedly among cytotoxic T cells. NK cells were sparsely found within the chordoma TIME and few were in an activated state. No immune composition differences were seen in chordomas originating from diverse anatomic sites or between those resected at primary versus advanced disease stage.ConclusionThis is the first comprehensive evaluation of the chordoma TIME including myeloid, T cell, and NK cell appraisal using MIF. Our findings demonstrate that myeloid cells significantly infiltrate chordoma tumor parenchyma while T cells tend to be tumor parenchymal excluded with high stromal infiltration. On average, myeloid cells are found nearer to target tumor cells than T cells, potentially resulting in restriction of T effector cell function. This study suggests that future immunotherapy combinations for chordoma should be aimed at decreasing myeloid cell suppressive function while enhancing cytotoxic T cell and NK cell killing.

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“…Studies of the chordoma immune microenvironment to date have focused on the PD-1 axis ( 90 , 91 ), as well as other potentially important immune checkpoints such as B7-H3 and HHLA2 ( 92 , 93 ). A recent single-cell transcriptomic analysis of six chordoma tumors identified putative immunosuppressive contributions from regulatory T cells, tumor-associated macrophages, and TGFβ signaling ( 94 ). Notably, TGFβ pathway genes are upregulated by brachyury ( 81 ).…”

Section: Moving Beyond Genomics To Identify New Therapeutic Strategiesmentioning

confidence: 99%

Emerging target discovery and drug repurposing opportunities in chordoma

Freed

Sommer²,

Punturi³

2022

Front. Oncol.

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The development of effective and personalized treatment options for patients with rare cancers like chordoma is hampered by numerous challenges. Biomarker-guided repurposing of therapies approved in other indications remains the fastest path to redefining the treatment paradigm, but chordoma’s low mutation burden limits the impact of genomics in target discovery and precision oncology efforts. As our knowledge of oncogenic mechanisms across various malignancies has matured, it’s become increasingly clear that numerous properties of tumors transcend their genomes – leading to new and uncharted frontiers of therapeutic opportunity. In this review, we discuss how the implementation of cutting-edge tools and approaches is opening new windows into chordoma’s vulnerabilities. We also note how a convergence of emerging observations in chordoma and other cancers is leading to the identification and evaluation of new therapeutic hypotheses for this rare cancer.

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Single-cell transcriptome profiling reveals intra-tumoral heterogeneity in human chordomas

Cited by 24 publications

References 56 publications

Chordoma recruits and polarizes tumor-associated macrophages via secreting CCL5 to promote malignant progression

Chordoma recruits and polarizes tumor-associated macrophages via secreting CCL5 to promote malignant progression

Multi-spectral immunofluorescence evaluation of the myeloid, T cell, and natural killer cell tumor immune microenvironment in chordoma may guide immunotherapeutic strategies

Emerging target discovery and drug repurposing opportunities in chordoma

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