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

Nakamura, Minoru; Magara, Tetsuya; Kano, Shinji; Matsubara, Akihiro; Katô, Hiroshi; Morita, Akimichi

doi:10.3389/fonc.2022.811586

Cited by 10 publications

(8 citation statements)

References 37 publications

(40 reference statements)

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“… 46 Importantly, CD4 T cells are crucial for the formation of tertiary lymphoid structures in the tumor microenvironment. 47–49 These structures of coordinated B and CD4 T cells are associated with improved survival across several cancer types including MCC 50 and likely lead to improved antitumor immunity via increased support for cancer-specific CD8 T cells. 51 …”

Section: Discussionmentioning

confidence: 99%

“…46 Importantly, CD4 T cells are crucial for the formation of tertiary lymphoid structures in the tumor microenvironment. [47][48][49] These structures of coordinated B and CD4 T cells are associated with improved survival across several cancer types including MCC 50 and likely lead to improved antitumor immunity via increased support for cancer-specific CD8 T cells. 51 To determine which of many roles neoantigenspecific CD4 T cells were playing in this patient's clinical response, we phenotyped these cells via scRNAseq (figures 3B and 4A).…”

Section: Discussionmentioning

confidence: 99%

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Transcriptional and functional analyses of neoantigen-specific CD4 T cells during a profound response to anti-PD-L1 in metastatic Merkel cell carcinoma

Church

Pulliam

Longino

et al. 2022

J Immunother Cancer

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BackgroundMerkel cell carcinoma (MCC) often responds to PD-1 pathway blockade, regardless of tumor-viral status (~80% of cases driven by the Merkel cell polyomavirus (MCPyV)). Prior studies have characterized tumor-specific T cell responses to MCPyV, which have typically been CD8, but little is known about the T cell response to UV-induced neoantigens.MethodsA patient in her mid-50s with virus-negative (VN) MCC developed large liver metastases after a brief initial response to chemotherapy. She received anti-PD-L1 (avelumab) and had a partial response within 4 weeks. Whole exome sequencing (WES) was performed to determine potential neoantigen peptides. Characterization of peripheral blood neoantigen T cell responses was evaluated via interferon-gamma (IFNγ) ELISpot, flow cytometry and single-cell RNA sequencing. Tumor-resident T cells were characterized by multiplexed immunohistochemistry.ResultsWES identified 1027 tumor-specific somatic mutations, similar to the published average of 1121 for VN-MCCs. Peptide prediction with a binding cut-off of ≤100 nM resulted in 77 peptides that were synthesized for T cell assays. Although peptides were predicted based on class I HLAs, we identified circulating CD4 T cells targeting 5 of 77 neoantigens. In contrast, no neoantigen-specific CD8 T cell responses were detected. Neoantigen-specific CD4 T cells were undetectable in blood before anti-PD-L1 therapy but became readily detectible shortly after starting therapy. T cells produced robust IFNγ when stimulated by neoantigen (mutant) peptides but not by the normal (wild-type) peptides. Single cell RNAseq showed neoantigen-reactive T cells expressed the Th1-associated transcription factor (T-bet) and associated cytokines. These CD4 T cells did not significantly exhibit cytotoxicity or non-Th1 markers. Within the pretreatment tumor, resident CD4 T cells were also Th1-skewed and expressed T-bet.ConclusionsWe identified and characterized tumor-specific Th1-skewed CD4 T cells targeting multiple neoantigens in a patient who experienced a profound and durable partial response to anti-PD-L1 therapy. To our knowledge, this is the first report of neoantigen-specific T cell responses in MCC. Although CD4 and CD8 T cells recognizing viral tumor antigens are often detectible in virus-positive MCC, only CD4 T cells recognizing neoantigens were detected in this patient. These findings suggest that CD4 T cells can play an important role in the response to anti-PD-(L)1 therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Transcriptional and functional analyses of neoantigen-specific CD4 T cells during a profound response to anti-PD-L1 in metastatic Merkel cell carcinoma

Church

Pulliam

Longino

et al. 2022

J Immunother Cancer

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“…Additionally, they observed that TLS were significantly associated with higher CD8:CD4 T-cell ratio in the tumor periphery, but not within the tumor center [ 102 ]. Recently, Nakamura et al examined both virus-positive and negative cases and determined that there are five chemokine genes— CCL5 , CCR2 , CCR7 , CXCL9 , and CXCL13 —with significantly higher expressions in TLS-positive samples compared to TLS-negative samples [ 103 ]. Regardless of the expression of TLS in MCPyV-positive tissue samples, virus-positive tissue samples had a similar prognosis.…”

Section: Formation Of Tertiary Lymphoid Structuresmentioning

confidence: 99%

“…Interestingly, the chemokine genes CXCL10 and CX3CR1 had different expression levels in the presence of MCPyV infection (compared to lack of infection) in TLS-negative samples. It was also shown that patients with high CXCL13 or CCL5 expression had better prognosis compared to those with lower expression, suggesting that chemokine expression profiles may offer insights into the TME and thereby may represent a potential prognostic marker [ 103 ].…”

Section: Formation Of Tertiary Lymphoid Structuresmentioning

confidence: 99%

T-Cell Mediated Immunity in Merkel Cell Carcinoma

Ouyang

Zheng

Agak

2022

Cancers

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Merkel cell carcinoma (MCC) is a rare and frequently lethal skin cancer with neuroendocrine characteristics. MCC can originate from either the presence of MCC polyomavirus (MCPyV) DNA or chronic ultraviolet (UV) exposure that can cause DNA mutations. MCC is predominant in sun-exposed regions of the body and can metastasize to regional lymph nodes, liver, lungs, bone, and brain. Older, light-skinned individuals with a history of significant sun exposure are at the highest risk. Previous studies have shown that tumors containing a high number of tumor-infiltrating T-cells have favorable survival, even in the absence of MCPyV DNA, suggesting that MCPyV infection enhances T-cell infiltration. However, other factors may also play a role in the host antitumor response. Herein, we review the impact of tumor infiltrating lymphocytes (TILs), mainly the CD4+, CD8+, and regulatory T-cell (Tregs) responses on the course of MCC, including their role in initiating MCPyV-specific immune responses. Furthermore, potential research avenues related to T-cell biology in MCC, as well as relevant immunotherapies are discussed.

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“…Although spontaneous regression is thought to occur as a result of the high immune activity of MCC, 3,4 the tumour immune microenvironment has not been analysed in detail. We previously analysed tumour immune activity in 41 samples by comprehensive RNA sequencing using a next‐generation sequencer, 5 and the presence of tertiary lymphoid structures (TLS) in 61 cases of MCC 6 . As a result, MCC can be divided into groups with high‐ and low‐immune activity, 5 MCPyV‐positive cases had a good prognosis with or without TLS, MCPyV‐negative, TLS‐positive cases had a good prognosis comparable to MCPyV‐positive cases, and MCPyV‐negative and TLS‐negative cases had a worse prognosis than the other cases 6 .…”

Section: Introductionmentioning

confidence: 99%

Analyses of tertiary lymphoid structures observed in cases of Merkel cell carcinoma showing spontaneous regression

Nakamura,

Yoshimitsu,

Magara

et al. 2024

Experimental Dermatology

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Merkel cell carcinoma (MCC) is a high‐grade skin cancer, but spontaneous regression is observed at a markedly higher frequency than in other carcinomas. Although spontaneous regression is a phenomenon that greatly impacts treatment planning, we still cannot predict it. We previously reported on the prognostic impact of the presence or absence of tertiary lymphoid structures (TLS) and of Merkel cell polyomavirus (MCPyV) infection. To learn more about the spontaneous regression of MCC, detailed analyses were performed focusing on spontaneous regression cases. We collected 71 Japanese patients with MCC including 6 cases of spontaneous regression. Samples were analysed by immunostaining, spatial single‐cell analysis using PhenoCycler, and RNA sequencing using the next‐generation sequencer (NGS). All 6 cases of spontaneous regression were positive for MCPyV. TLS was positive in all 5 cases analysed. Spatial single‐cell analyses revealed that PD‐L1‐positive tumour cells were in close proximity to CD20‐positive B cell and CD3‐, 4‐positive T cells. Gene set enrichment analysis between MCPyV‐positive and TLS‐positive samples and other samples showed significantly high enrichment of “B‐cell–mediated immunity” gene sets in the MCPyV‐positive and TLS‐positive groups. In conclusion, TLS may play an important role in the spontaneous regression of MCC.

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

Cited by 10 publications

References 37 publications

Transcriptional and functional analyses of neoantigen-specific CD4 T cells during a profound response to anti-PD-L1 in metastatic Merkel cell carcinoma

Transcriptional and functional analyses of neoantigen-specific CD4 T cells during a profound response to anti-PD-L1 in metastatic Merkel cell carcinoma

T-Cell Mediated Immunity in Merkel Cell Carcinoma

Analyses of tertiary lymphoid structures observed in cases of Merkel cell carcinoma showing spontaneous regression

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