Abstract
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.
Highlights
Merkel cell carcinoma (MCC) is a rare malignant skin cancer with potentially high immune activity [1].MCC is treated with immune checkpoint inhibitors (ICIs), but the response rate is only about 30% [2], and many patients exhibit no benefit
Our findings indicate that the presence of Tertiary lymphoid structures (TLSs) is a potential prognostic marker, even for Merkel cell polyoma virus (MCPyV)-negative cases
This study is the first to analyze the relationship between the presence of TLSs, MCPyV infection, and prognosis in MCC
Summary
Merkel cell carcinoma (MCC) is a rare malignant skin cancer with potentially high immune activity [1].MCC is treated with immune checkpoint inhibitors (ICIs), but the response rate is only about 30% [2], and many patients exhibit no benefit. The presence or absence of Merkel cell polyoma virus (MCPyV) infection is reported to be closely related to the tumor mutation burden and amount of neoantigens [3, 4]. MCPyV-negative, i.e., ultraviolet-induced, MCCs have a higher tumor mutation burden and more neoantigens than MCPyVpositive MCC. The presence of tertiary lymphoid structures (TLSs) in the tumor tissue of many cancers is considered to indicate a better prognosis and a good response to ICIs [6, 7]. A previous study reported that the presence of TLSs correlates with a good prognosis in MCC, but the 21 cases examined in that study were all MCPyV-positive cases [9]. We examined the correlation between the presence or absence of TLSs and prognosis in 61 MCC cases, including both MCPyV-positive and MCPyVnegative cases.
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