Dataset Information

Cancer Microenvironment Defines Tumor-Infiltrating Lymphocyte Density and Tertiary Lymphoid Structure Formation in Laryngeal Cancer.

ABSTRACT:

Background

The presence and activity of tumor-infiltrating lymphocytes (TILs) is a key parameter related to the antitumor immune response. A large number of studies reveal TIL density as a prognostic marker and predictor of response to radiotherapy, chemotherapy, and immunotherapy.

Methods

We examined the TIL and tertiary lymphoid structure TLS density in the invading front and inner tumor stroma, in a 33 squamous cell laryngeal carcinomas (LSCC) treated with laryngectomy. TIL and TLS densities were in parallel examined with markers of anaerobic metabolism, vascular density (VD), vascular survival ability (VSA), and histopathological parameters.

Results

TIL and TLS densities significantly decreased in inner tumor areas (p < 0.0001). TIL density in the invading tumor front was inversely related with lymph node involvement (p = 0.03), HIF1α expression (p = 0.008), vessel density (p = 0.02), and MIB1 (p = 0.006). TIL density in inner stroma was inversely linked to local invasion (marginal p = 0.05), tumor budding (TB) (p = 0.005), MIB1 (p = 0.02), and HIF1α expression (p = 0.02). Low-TLS density in the invading front and in inner tumor areas was related to high TB (p = 0.02 and 0.002, respectively), HIF1α (p = 0.003 and 0.01, respectively), and LDH5 expression (p = 0.003 and 0.007, respectively). CD4⁺, FOXP3⁺ TIL density, and FOXP3⁺/CD8⁺ ratio were directly associated with VSA (p = 0.008, 0.02, and 0.05, respectively).

Conclusion

Poor immune response is related to hypoxic background and anaerobic metabolism, as well as increased invasive and metastatic ability. Regulatory TIL markers are linked with increased angiogenic potential. The prognostic, predictive, and therapy-guiding value of TILs in clinical practice demands thorough investigation.

SUBMITTER: Gkegka AG

PROVIDER: S-EPMC10293152 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Publications

Cancer Microenvironment Defines Tumor-Infiltrating Lymphocyte Density and Tertiary Lymphoid Structure Formation in Laryngeal Cancer.

Gkegka Anastasia G AG Koukourakis Michael I MI Katotomichelakis Michael M Giatromanolaki Alexandra A

Head and neck pathology 20221231 2

<h4>Background</h4>The presence and activity of tumor-infiltrating lymphocytes (TILs) is a key parameter related to the antitumor immune response. A large number of studies reveal TIL density as a prognostic marker and predictor of response to radiotherapy, chemotherapy, and immunotherapy.<h4>Methods</h4>We examined the TIL and tertiary lymphoid structure TLS density in the invading front and inner tumor stroma, in a 33 squamous cell laryngeal carcinomas (LSCC) treated with laryngectomy. TIL and ...[more]

PMID: 36586079

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Project description: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.

Project description:BackgroundCholangiocarcinoma is a challenging malignancy with limited responses to conventional therapies, particularly immune checkpoint inhibitor therapy. Tumor-infiltrating lymphocytes (TILs) and tertiary lymphoid structures (TLSs) are key components of the tumor microenvironment (TME) and have been implicated in the immune response to cancer. However, the role and difference of TLSs and TILs in patients with cholangiocarcinoma remains unclear. This study elucidates their contributions to the TME.MethodsWe examined 16 tumor samples from a single-arm, phase II trial of nivolumab plus modified gemcitabine and S-1 and various datasets. Immunohistochemistry and RNA sequencing were employed to assess TLSs and TILs presence and activity. Differential gene expression and signature of immune cell composition were examined by GeoMx Digital Spatial Profiler and Cancer Transcriptome Altas analysis.ResultsTLS-positive (N=7) patients demonstrated significantly better immunotherapy outcomes compared with TLS-negative (N=9) patients, including higher objective response rates (71% vs 0%) and disease control rates (100% vs 67%). The presence of TLSs correlated with improved progression-free and overall survival (p=0.03). TLSs were associated with "inflamed" tumors characterized by substantial immune infiltration, particularly involving T and B cells. Gene expression analyses identified significant upregulation of B cell-related genes in TLSs. Additionally, TLSs exhibited higher properties of memory B cells and myeloid dendritic cells but lower levels of innate immune cells compared with TILs. T cells within TLSs showed elevated expression of precursor-exhausted-related genes and lower cytotoxicity signature. Furthermore, TILs in TLS-positive tumors had higher levels of exhaustion signatures compared with TILs in TLS-negative tumors. Clinical data corroborated these findings, with higher PD-L1 and LAG-3 expression in TLS-positive tumors.ConclusionOur findings revealed that TILs in TLS-positive tumors have more exhausted T cell signature and PD-1 and LAG-3 protein expression in CCA which support our clinical finding. TLSs can predict favorable immunotherapy responses in patients with cholangiocarcinoma, highlighting their potential as a biomarker and therapeutic target to enhance treatment efficacy.

Dataset Information

Cancer Microenvironment Defines Tumor-Infiltrating Lymphocyte Density and Tertiary Lymphoid Structure Formation in Laryngeal Cancer.

Background

Methods

Results

Conclusion

Publications

Cancer Microenvironment Defines Tumor-Infiltrating Lymphocyte Density and Tertiary Lymphoid Structure Formation in Laryngeal Cancer.

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