Predictive value of <scp>CD8</scp>/<scp>FOXP3</scp> ratio combined with <scp>PD‐L1</scp> expression for radiosensitivity in patients with squamous cell carcinoma of the larynx receiving definitive radiation therapy

Ono, Takeharu; Azuma, Koichi; Kawahara, Akihiko; Kakuma, Tatsuyuki; Satô, Fumihiko; Akiba, Jun; Tanaka, Norimitsu; Abe, Toshi; Chitose, Shun‐ichi; Umeno, Hirohito

doi:10.1002/hed.26416

Cited by 7 publications

(7 citation statements)

References 51 publications

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“…The studies that did not fulfill all the inclusion criteria were discarded. Of these, seven were excluded because they did not report the outcome of LSCC separately from other locations of HNSCC [12,[15][16][17][18][19][20], eight because no HRs were available [21][22][23][24][25][26][27][28][29], one study because they reported outcome in terms of local control [30], one study that evaluated Il-12R expression on tumor cells [31], and one study that evaluated lymphocytes in peripheral blood [32]. This left 11 studies for the analysis (Fig- Studies were selected if they met the following inclusion criteria: (1) prognostic value of TIL was evaluated in patients with LSCC (primary or recurrent), (2) TIL were evaluated either immunohistochemically (CD8+, CD4+, and/or CD3+) and/or in hematoxylin-and eosin (HE)-stained sections, in resected specimens or in diagnostic biopsies, (3) TIL were evaluated either in tumor epithelium and/or tumor stroma, (4) prognostic value of TIL was evaluated by time-to-event survival analysis with overall survival (OS) and/or disease-free survival (DFS), and (5) original articles published in English.…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Tumor-Infiltrating Lymphocytes in the Tumor Microenvironment of Laryngeal Squamous Cell Carcinoma: Systematic Review and Meta-Analysis

et al. 2021

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The presence of tumor-infiltrating lymphocytes (TIL) in the tumor microenvironment has been demonstrated to be of prognostic value in various cancers. In this systematic review and meta-analysis, we investigated the prognostic value of TIL in laryngeal squamous cell carcinoma (LSCC). We performed a systematic search in PubMed for publications that investigated the prognostic value of TIL in LSCC. A meta-analysis was performed including all studies assessing the association between TIL counts in hematoxylin-eosin (HE)-stained sections, for CD8+ and/or CD3+/CD4+ TIL and overall survival (OS) or disease-free survival (DFS). The pooled meta-analysis showed a favorable prognostic role for stromal TIL in HE sections for OS (HR 0.57, 95% CI 0.36–0.91, p = 0.02), and for DFS (HR 0.56, 95% CI 0.34–0.94, p = 0.03). High CD8+ TIL were associated with a prolonged OS (HR 0.62, 95% CI 0.4–0.97, p = 0.04) and DFS (HR 0.73, 95% CI 0.34–0.94, p = 0.002). High CD3+/CD4+ TIL demonstrated improved OS (HR 0.32, 95% CI 0.16–0.9, p = 0.03) and DFS (HR 0.23, 95% CI 0.10–0.53, p = 0.0005). This meta-analysis confirmed the favorable prognostic significance of TIL in LSCC. High stromal TIL evaluated in HE sections and intra-tumoral and stromal CD3+, CD4+ and/or CD8+ TIL might predict a better clinical outcome.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Tumor-Infiltrating Lymphocytes in the Tumor Microenvironment of Laryngeal Squamous Cell Carcinoma: Systematic Review and Meta-Analysis

et al. 2021

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“…It is reported that it might be a useful biomarker of radiosensitivity in patients with laryngeal SCC receiving definitive RT. 39 In our study, most patients received RT, and the subset of PD-L1 þ patients could benefit from a combination of radiotherapy and anti-PD-L1 treatment. Further studies on CD8/FOXP3 expression on ASCC are needed to explore future therapeutic venues.…”

Section: Pd-l1 Expression and Outcomesmentioning

confidence: 82%

“…The numerical and functional abnormality of Tregs may be influenced by radiation dose, the form of radiation, or tumor type. 39,40 A previous study of HIV-positive patients with cervical squamous cell carcinoma showed that PD-L1 þ tumor cells are more radiosensitive and that those patients show better response with RT. 35 High CD8:FOXP3 ratio combined with negative PD-L1 expression was an independent and significant favorable predictive factor for local control.…”

Section: Pd-l1 Expression and Outcomesmentioning

confidence: 99%

Programmed Death Ligand-1 Expression Is Associated With Poorer Survival in Anal Squamous Cell Carcinoma

Monsrud

Avadhani

Mošunjac

et al. 2021

Archives of Pathology &Amp; Laboratory Medicine

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Context.— Upregulation of programmed death ligand-1 (PD-L1), an immunoregulatory protein, is associated with an adverse outcome in several malignancies. Very few studies have evaluated PD-L1 expression in invasive anal squamous cell carcinoma (ASCC). Objective.— To assess PD-L1 expression in patients with ASCC and correlate it with clinicopathologic factors and clinical outcomes. Design.— Fifty-one cases of ASCC were immunostained for PD-L1. PD-L1 expression by combined positive score and tumor proportion score was correlated with age, gender, HIV status, HIV viral load, CD4 count, stage, and outcomes. Kaplan-Meier curves for overall survival were plotted and compared using the log-rank test. Cox regression analysis was performed to identify significant prognostic factors (2-tailed P < .05 was considered statistically significant). Results.— PD-L1 was positive in 24 of 51 cases (47%) by combined positive score and in 18 of 51 (35%) by tumor proportion score. The median cancer-specific survival and 5-year overall survival were significantly lower in PD-L1+ patients. Age, gender, HIV status, HIV viral load, stage, and cancer progression were not significantly different between the two groups. CD4 count of more than 200/μL was significantly higher in PD-L1+ patients. PD-L1+ status remained statistically significant for worse overall survival on multivariate analysis. Conclusions.— PD-L1+ status is an independent adverse prognostic factor for overall survival in ASCC. This study highlights the potential of PD-L1 targeted therapy in better management of ASCC.

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“…Furthermore, we have shown that the density of tumor infiltrate within nasopharyngeal cancer tumor microenvironment was also associated with tumor progression [5]. Various data has indicated that the immune contexture within tumor microenvironment in most solid cancer has a great role predicting treatment outcomes [14][15][16][17][18]. For instance, higher density of infiltrating tumor T regulatory FOXP3 cells was shown to negatively affect prognosis in breast cancer [19].…”

Section: Introductionmentioning

confidence: 95%

Immune cells markers within local tumor microenvironment are associated with EBV oncoprotein in nasopharyngeal cancer

et al. 2022

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Introduction EBV infection in nasopharyngeal cancer ensued in latent infection mode. In this latent infection various EBV oncoproteins such as EBNA1 and LMP1 was expressed. EBV oncoproteins could theoretically recruit immune cells, which might help to control cancer. Therefore, this study was aimed to elucidate the association with EBV oncoproteins (EBNA1 and LMP1), immune markers (CD4, CD8, and FOXP3) from nasopharyngeal cancer microenvironment with tumor progression. Method Nasopharyngeal biopsy was obtained from patients suspected to have nasopharyngeal cancer. Those samples with microscopically confirmed nasopharyngeal cancer were tested for EBNA1, LMP1, CD4, CD8, and FOXP3 concentration with ELISA, then verified with IHC. Each patient tumor volume was assessed for primary nasopharyngeal tumor volume (GTVp) and neck nodal metastases tumor volume (GTVn). Correlation test with Spearman correlation and scatterplot were carried out. Result Total 23 samples with nasopharyngeal cancer were analyzed. There was moderate correlation (ρ = 0.45; p value = 0.032) between LMP1 and GTVp. There was strong correlation (ρ = 0.81; p value < 0.001) between CD8 and GTVp. There was also moderate correlation (ρ = 0.6; p value = 0.002) between FOXP3 and GTVp. The CD8 concentration has moderate correlation with both EBNA1 (ρ = 0.46; p value = 0.026) and LMP1 (ρ = 0.47; p value = 0.023). While FOXP3 has moderate correlation with only LMP1 (ρ = 0.58; p value = 0.004). No correlation was found between all the markers tested here with GTVn. Discussion We found larger primary nasopharyngeal tumor was associated with higher CD8 marker. This was thought due to the presence of abundance CD8 T cells in the nasopharynx, but those abundance CD8 T cells were suspected to be dysfunctional. The nasopharyngeal cancer was also known to upregulate chemokines that could recruit T regulatory FOXP3 cells. Furthermore, T regulatory FOXP3 cells differentiation was induced through several pathways which was triggered by EBNA1. The correlation found in this study could guide further study to understand nasopharyngeal carcinogenesis and the relationship with our immune system.

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Predictive value of CD8/FOXP3 ratio combined with PD‐L1 expression for radiosensitivity in patients with squamous cell carcinoma of the larynx receiving definitive radiation therapy

Cited by 7 publications

References 51 publications

Tumor-Infiltrating Lymphocytes in the Tumor Microenvironment of Laryngeal Squamous Cell Carcinoma: Systematic Review and Meta-Analysis

Tumor-Infiltrating Lymphocytes in the Tumor Microenvironment of Laryngeal Squamous Cell Carcinoma: Systematic Review and Meta-Analysis

Programmed Death Ligand-1 Expression Is Associated With Poorer Survival in Anal Squamous Cell Carcinoma

Immune cells markers within local tumor microenvironment are associated with EBV oncoprotein in nasopharyngeal cancer

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