Tertiary lymphoid structures correlate with better prognosis in cutaneous angiosarcoma

Magara, Tetsuya; Nakamura, Minoru; Nojiri, Yu; Yoshimitsu, Makoto; Kano, Shinji; Matsubara, Akihiro; Katô, Hiroshi; Morita, Akimichi

doi:10.1016/j.jdermsci.2021.05.006

Cited by 9 publications

(11 citation statements)

References 7 publications

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“…The cohort is summarized in Supplementary Table 1 . This is the cohort of our previous report with one additional lymph node metastasis sample ( 4 ). Immunostaining was performed in this cohort.…”

Section: Methodsmentioning

confidence: 99%

“…CD8-positive cells were counted in several locations with a high infiltrating cell density. Samples with at least one CD8-positive cell in a 200x high-power field (0.40mm 2 field area) were defined as ‘CD8-positive’, as previously described ( 4 ).…”

Section: Methodsmentioning

confidence: 99%

“…In the last few years, there have been several reports of immune checkpoint inhibitors (ICIs) being effective in CAS cases (1)(2)(3), which is expected to be a new effective therapy. Although CAS, as well as other soft tissue sarcomas, has been considered an immunologically "cold" tumor, our previous study of 61 samples from 31 cases of CAS revealed that there are active anti-tumor immune responses with abundant immune cell infiltration, including the formation of tertiary lymphoid structures (TLSs) (4). TLSs are lymphoid follicle-like clusters of CD20-positive B cells that form near the tumor or inflammatory lesions and are typically surrounded by CD3positive T cells.…”

Section: Introductionmentioning

confidence: 99%

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Tumor immune microenvironment of cutaneous angiosarcoma with cancer testis antigens and the formation of tertiary lymphoid structures

et al. 2023

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Cutaneous angiosarcoma (CAS) is a highly malignant tumor with few effective treatments. Although the indication for immune checkpoint inhibitors such as anti-PD-1 antibodies is expected to expand, there are many unknowns regarding the tumor immune microenvironment in CAS, which is generally considered an immunologically “cold” tumor. Our previous study demonstrated that tertiary lymphoid structures (TLSs) were associated with a favorable prognosis in CAS. However, we still don’t know what the difference is between cases of TLS-rich and TLS-poor. Furthermore, the number of TLSs can vary significantly between lesions in the same case, for example, between primary and recurrence. To analyze the changes in the tumor immune microenvironment in CAS in more detail, we performed comprehensive RNA sequencing using a Next-generation sequencer (NGS). Sixty-two samples from 31 cases of CAS treated at Nagoya City University were collected. NGS and gene set enrichment analysis (GSEA) were performed on 15 samples among them. Immunohistochemistry and prognostic analysis by Kaplan-Meier method were performed on all 62 samples. NGS results showed that NY-ESO-1 (CTAG1B) was significantly upregulated in the TLS-positive cases. Immune checkpoint molecules including programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) were upregulated in TLS-negative or TLS-low cases and seemed to associate with the suppression of TLS formation. In a comparison of primary and recurrent lesions, other cancer-testis antigens (CTAs) including XAGE-1B were significantly upregulated in recurrent lesions. The number of infiltrating CD8-positive cells and TLSs showed no significant trend between primary and recurrent lesions. However, the PD-L1 expression of tumor cells was significantly lower in recurrent than in primary lesions. Chemokines correlated with NY-ESO-1 expression were CCL21 and CXCL8, and only CCL21 correlated with the number of TLS. There was no chemokine associated with XAGE-1. NY-ESO-1 and XAGE-1 are detectable by immunohistochemistry. Although each cannot be a prognostic marker by itself, they can be a helpful marker in combination with the number of TLSs. CTAs play an essential role in forming the tumor immune microenvironment in CAS. These findings are evidence that CAS is an immunologically “hot” tumor and provides us with potential therapeutic targets and encourages the expansion of immunotherapy indications.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Tumor immune microenvironment of cutaneous angiosarcoma with cancer testis antigens and the formation of tertiary lymphoid structures

et al. 2023

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“…TLSs were typically identified as clusters of CD20-positive cells surrounded by CD3-positive cells. Including immature TLSs, in which only a few CD3-positive cells surround a CD20-positive cell cluster, if a lesion had at least one TLS, it was counted as TLS-positive, as previously described ( 12 ). The fluorescence intensities of PD-L1 were calculated from 10 randomly selected fields using ImageJ Software (NIH, Bethesda, MD, USA) as previously described ( 11 ).…”

Section: Methodsmentioning

confidence: 99%

Tertiary Lymphoid Structures and Chemokine Landscape in Virus-Positive and Virus-Negative Merkel Cell Carcinoma

et al. 2022

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Tertiary lymphoid structures (TLSs) are used as biomarkers in many cancers for predicting the prognosis and assessing the response to immunotherapy. In Merkel cell carcinoma (MCC), TLSs have only been examined in MCPyV-positive cases. Here, we examined the prognostic value of the presence or absence of TLSs in 61 patients with MCC, including MCPyV-positive and MCPyV-negative cases. TLS-positive samples had a significantly better prognosis than TLS-negative samples. MCPyV-positive samples had a good prognosis with or without TLSs, and MCPyV-negative/TLS-positive samples had a similarly good prognosis as MCPyV-positive samples. Only MCPyV-negative/TLS-negative samples had a significantly poor prognosis. All cases with spontaneous regression were MCPyV-positive/TLS-positive. We also performed a comprehensive analysis of the chemokines associated with TLS formation using next-generation sequencing (NGS). The RNA sequencing results revealed 5 chemokine genes, CCL5, CCR2, CCR7, CXCL9, and CXCL13, with significantly high expression in TLS-positive samples compared with TLS-negative samples in both MCPyV-positive and MCPyV-negative samples. Only 2 chemokine genes, CXCL10 and CX3CR1, had significantly different expression levels in the presence or absence of MCPyV infection in TLS-negative samples. Patients with high CXCL13 or CCL5 expression have a significantly better prognosis than those with low expression. In conclusion, the presence of TLSs can be a potential prognostic marker even in cohorts that include MCPyV-negative cases. Chemokine profiles may help us understand the tumor microenvironment in patients with MCPyV-positive or MCPyV-negative MCC and may be a useful prognostic marker in their own right.

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“…There has been increased interest in immune regulation as a potential therapeutic avenue in sarcoma treatment, prompting investigation of whether anti-programmed cell death protein 1 (PD-1) or ligand (PD-L1) immune checkpoint inhibitors may have a role in treatment. Suggested biomarkers of response to immunotherapy include tumor infiltrating lymphocytes (TILs), PD-L1 expression, microsatellite instability, immunogenic genomic profile, UV signature, inflamed hypermutated tumors, and tertiary lymphoid structures ( 16 ). Tumor mutational burden (TMB) high (≥10 mutations/Megabase (Muts/Mb)) and microsatellite instability high (MSI-H) are biomarkers for which pembrolizumab ( 17 ), an anti-PD-1 agent, is approved in the tumor-agnostic setting ( 18 , 19 ).…”

Section: Introductionmentioning

confidence: 99%

Cutaneous angiosarcoma: A review of current evidence for treatment with checkpoint inhibitors

2023

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Cutaneous angiosarcoma (cAS) is a rare and aggressive subtype of soft tissue sarcoma with poor prognosis and suboptimal treatment options. Clinical presentation is variable, but cAS often arises from the head and neck. The most widely accepted current approach, surgical excision with adjuvant radiotherapy, is associated with high recurrence rates and can leave patients with profound disfigurement. Chemotherapy and targeted therapy alternatives have had limited success. Thus, there is a significant unmet need to address the absence of durable treatments for advanced and metastatic cAS. Like melanoma and cutaneous squamous cell carcinoma, tumor types with known response to immunotherapy, cAS harbors immune biomarkers, such as tumor mutational burden high (TMB-H), PD-L1 positivity, ultraviolet signature expression, and tertiary lymphoid structures. While data on the use and efficacy of immunotherapy in cAS is limited, the biomarkers suggest a promising advancement in future treatment options. This review aims to summarize and discuss current data from case reports, case series, retrospective studies and clinical trials regarding immunotherapy treatment and outcomes for cAS.

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Tertiary lymphoid structures correlate with better prognosis in cutaneous angiosarcoma

Cited by 9 publications

References 7 publications

Tumor immune microenvironment of cutaneous angiosarcoma with cancer testis antigens and the formation of tertiary lymphoid structures

Tumor immune microenvironment of cutaneous angiosarcoma with cancer testis antigens and the formation of tertiary lymphoid structures

Tertiary Lymphoid Structures and Chemokine Landscape in Virus-Positive and Virus-Negative Merkel Cell Carcinoma

Cutaneous angiosarcoma: A review of current evidence for treatment with checkpoint inhibitors

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