Prognostic Relevance of CD4+, CD8+ and FOXP3+ TILs in Oral Squamous Cell Carcinoma and Correlations with PD-L1 and Cancer Stem Cell Markers.
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SUBMITTER: Lequerica-Fernandez P
PROVIDER: S-EPMC8227658 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:PurposeCurrently, adjuvant chemotherapy is recommended for patients with high risk stage I non-small cell lung cancer (NSCLC). However, identifying high risk patients remains a challenge. This study aims to identify the patient cohorts more likely to benefit from adjuvant chemotherapy based on the tumor micro-immune environment.ResultsCD8+TILs significantly associated with disease-free survival (DFS) and overall survial (OS) (p=0.002; 0.040). Patients with high risk factors may also predict shorter DFS (P=0.056). When compared together, patients with high-CD8+TILs showed better DFS than patients with low-CD8+TILs, no matter their risk factors status. There's no correlation between PD-L1 expressions and survival. PD-L1 was highly expressed in men, squamous and well differentiated carcinoma. In addition, Foxp3+TILs alone didn't show any prognostic effects, but low-Foxp3/high-CD8+TILs were associated with prolonged DFS (p=0.031).MethodsA total of 126 patients with surgically resected stage I NSCLC were included to perform immunohistochemistry of CD8+ tumor infiltrating lymphocytes (TILs), programmed death ligand-1(PD-L1) and forkhead box P3 (Foxp3)+TILs.ConclusionCD8+TILs are effective prognostic predictors. Patients with surgically resected stage I NSCLC showing low CD8+TILs could be considered for adjuvant chemotherapy, even if they have no high risk features.
| S-EPMC5325445 | biostudies-literature
Project description:Objective:To investigate the association between programmed death-ligand 1 (PD-L1) coupled with CD8+ tumor-infiltrating lymphocytes (TILS) and the clinicopathological features, along with prognosis of cervical squamous cell carcinoma (CSCC). Methods:95 patients of CSCC received tumor resection at the Department of Pathology of the First Affiliated Hospital of University of Science and Technology of China (USTC) from 2015 to 2020. Full-automatic immunohistochemistry was applied to measure PD-L1 expression and CD8+ TILS density. Our literature deeply assessed the links between PD-L1 expression, clinicopathological features, and the influences of combination of PD-L1 and CD8+ TILS (PD-L1+/CD8+ TILS) on the prognosis of CSCC. Results:64.21% of CSCC patients (61/95) expressed PD-L1, and PD-L1 expression was related to the Federation of Gynecology and Obstetrics (FIGO) stage, tumor size, invasion depth, differentiation degree, metastasis of lymph node, and vascular invasion (P < 0.05). Dramatic correlation between PD-L1 expression and CD8+ TILS density was illustrated in CSCC patients (r = -0.461, P < 0.001). Obvious differences in differentiation degree, FIGO stage, infiltration depth, and lymph node metastasis were shown between patients with PD-L1 coupled with high-density of CD8+ TILS and those with PD-L1 coupled with low-density of CD8+ TILS (P < 0.05). Patients with PD-L1 negative expression exhibited better prognosis compared with those with PD-L1 positive expression (P < 0.05). Patients with PD-L1 coupled with high-density of CD8+ TILS showed better prognostic status, while those with PD-L1 coupled with low-density of CD8+ TILS had worse prognostic condition (P < 0.05). Differentiation, metastasis of lymph node, and FIGO stage were substantive impact elements of a CSCC patient's overall survival (OS) by Cox multivariate analysis. Conclusions:CD8+ TILS density is related to PD-L1 expression in carcinoma. PD-L1/CD8+ TILS density can be regarded as evaluation for the prognosis of patients with CSCC, providing a new therapeutic target in clinical application.
| S-EPMC7455844 | biostudies-literature
Project description:Data describing relationships between the tumor immune microenvironment and patient outcome are limited for esophageal squamous cell cancer (ESCC). The present study investigated the prognostic values of programmed death-ligand 1 (PD-L1) expression and CD8+ or forkhead box protein 3+ (FOXP3+) tumor-infiltrating lymphocytes (TILs) in 133 pathological T3N0M0 stage ESCC patients who underwent radical resection without neoadjuvant or adjuvant therapy. CD8+ and FOXP3+ TIL densities as well as PD-L1 levels in tumor cells and lymphocytes, were assessed through immunohistochemical staining. Patient survival was not associated with CD8+ or FOXP3+ TILs alone, but PD-L1 expression and the CD8+/FOXP3+ ratio were independent predictors of both disease-free and overall survival. PD-L1 expression correlated with age (p = 0.029), tumor length (p < 0.001), tumor differentiation status (p = 0.002) and reduced intratumoral CD8+ TIL density (p < 0.001). Our results suggest pT3N0M0 ESCC clinical outcomes correlate with CD8+ and FOXP3+ TIL densities and PD-L1 levels. Moreover, an intrinsic mechanism for induction of PD-L1 overexpression may be occurring during early tumor oncogenesis. This information may be useful for stratifying patients and guide the application of checkpoint blockade therapy in ESCC.
| S-EPMC5342092 | biostudies-literature
Project description:Oral tongue squamous cell carcinoma (OTSCC) is the most common oral cavity tumor. In this study, we examined the basis for the activity of programmed cell death protein (PD-1)-based immune checkpoint therapy that is being explored widely in head and neck cancers. Using multispectral imaging, we systematically investigated the OTSCC tumor microenvironment (TME) by evaluating the frequency of PD-1 expression in CD8+, CD4+, and FoxP3+ tumor-infiltrating lymphocytes (TIL). We also defined the cellular sources of PD-1 ligand (PD-L1) to evaluate the utility of PD-1:PD-L1 blocking antibody therapy in this patient population. PD-L1 was expressed in 79% of the OTSCC specimens examined within the TME. Expression of PD-L1 was associated with moderate to high levels of CD4+ and CD8+ TILs. We found that CD4+ TILs were present in equal or greater frequencies than CD8+ TILs in 94% of OTSCC and that CD4+FOXP3neg TILs were colocalized with PD-1/PD-L1/CD68 more frequently than CD8+ TILs. Both CD4+PD1+ and CD8+PD1+ TILs were anergic in the setting of PD-L1 expression. Overall, our results highlight the importance of CD4+ TILs as pivotal regulators of PD-L1 levels and in determining the responsiveness of OTSCC to PD1-based immune checkpoint therapy. Cancer Res; 77(22); 6365-74. ©2017 AACR.
| S-EPMC5690870 | biostudies-literature
Project description:The combination of perioperative chemotherapy plus complete surgical resection is currently accounted as the first-choice strategy in patients with locally advanced Gastric Cancer (LAGC). Nevertheless, the partial response rate makes it necessary to search biological parameters useful to select patients who would benefit most from neoadjuvant chemotherapy (NAD-CT). We performed a retrospective analysis on a cohort of 65 LAGC cases, EBV negative and without MMR defect, submitted to perioperative chemotherapy plus surgical resection. We evaluated the neutrophil-lymphocytes ratio (NLR) in peripheral blood, the TILs density (reported as CD4/CD8 tissue ratio) and PD-L1 expression by immunohistochemistry on bioptic tissues before the treatment. Results were correlated with the biological features, histological response (TRG) and clinical outcome (PFS and OS). We found that NLR, TILs and PD-L1 expression showed a significant correlation with TNM stage, lymphovascular invasion and response to NAD-CT (TRG). Correlating the NLR, TILs and PD-L1 expression with PFS and OS, we found that patients with lower NLR levels (< 2.5 ratio), lower TILs (< 0.2 ratio) and higher PD-L1 level (CPS ≥ 1) had a significantly better PFS and OS than those with higher NLR, higher TILs and lower PD-L1 expression (p < 0.0001). Multivariate and multiple regression analyses confirmed the predictive and prognostic role of all three parameters, especially when all three parameters are combined. Our study demonstrated that pre-treatment NLR, TILs and PD-L1 expression are predictive and prognostic parameters in NAD-CT-treated LAGC suggesting a pivotal role of the systemic and tumor microenvironment immunological profile in the response to chemotherapy.
| S-EPMC8738448 | biostudies-literature
Project description:BackgroundDNA mismatch repair (MMR) deficiency (dMMR) has been recognized as an important biomarker for immunotherapy in esophageal squamous cell carcinoma (ESCC), along with programmed death ligand 1 (PD-L1) expression and/or tumor-infiltrated lymphocytes (TILs). However, in ESCC, MMR protein assessment has not been well studied at present.MethodsA total of 484 ESCC tissues treated between 2007 and 2010, in our hospital, were enrolled. Immunohistochemical expression of MLH1, MSH2, MSH6, PMS2, and PD-L1 on tissue microarray specimens and clinicopathological features, including TILs, were analyzed retrospectively.ResultsOut of the 484 studied cases, loss of MLH1, MSH2, MSH6, and PMS2 expression were found in 6.8%, 2.1%, 8.7%, and 4.8% patients, respectively. dMMR was found in 65 patients, 37 cases involved in one MMR protein, 17 cases involved in two proteins, 7 cases involved in three proteins, and 4 cases involved in four proteins. There was no significant survival difference between pMMR (MMR-proficient) and dMMR patients (P>0.05). However, 224 patients with low PMS2 expression had better DFS and OS than 260 patients with high PMS2 expression (P=0.006 for DFS and 0.008 for OS), which was identified as an independent prognostic factor in multivariate analyses. Positive PD-L1 expression was detected in 341 (70.5%) samples. In stage I-II disease, patients with PD-L1 expression had better DFS and OS than those without PD-L1 expression(P<0.05), which was not found in stage III-IV disease. With the ITWG system, 40.1% of cases were classified as high TILs. Patients in the high-TILs group tended to have better DFS (P=0.055) and OS (P=0.070) than those in the low-TILs group and the differences were statistically significant in pMMR, high MSH6, or PMS2 expression cases (P<0.05). Also, high PMS2 expression patients with both PD-L1 expression and high TILs, had similar DFS and OS compared with low PMS2 expression patients (P>0.05), which were much better than other high PMS2 expression patients.ConclusionThe expression level of MMR proteins could also be used as a prognostic factor in ESCC and PMS2 expression outperformed other MMR proteins for predicting survival. The combination of PD-L1 expression and TILs may lead to more efficient risk stratification of ESCC.
| S-EPMC9294642 | biostudies-literature
Project description:Despite its rare incidence worldwide, penile squamous cell carcinoma (PeSCC) still presents with significant morbidity and mortality due to the limited treatment options for advanced patients, especially those in developing countries. The program death-1 (PD-1)/PD-1 ligand (PD-L1) axis has been demonstrated to play an important role in tumor immune escape, and immunotherapies targeting this pathway have shown great success in certain cancer types. Here, we analyzed the expression pattern of PD-L1 in tumor cells and tumor-infiltrating lymphocytes (TILs) in PeSCC with a multi-center cohort. We found that the majority of PeSCCs (53.4%) were PD-L1-positive and that high PD-L1 expression in tumor cells was associated with a poor prognosis. Notably, PD-L1 expression in tumor cells was significantly associated with the extent of TILs and CD8+ TILs. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) showed that PD-L1 was positively correlated with interferon-gamma (IFNγ) and CD8+ gene expression. Moreover, we defined the constitutive and inducible surface expression of PD-L1 in newly established primary PeSCC cell lines. Interestingly, two PeSCC cell lines had high intrinsic PD-L1 expression. Another cell line showed low PD-L1 expression, but the PD-L1 expression could be induced by IFNγ stimulation. Overall, our data showed that high PD-L1 expression in penile tumor cells indicated a poor prognosis. The upregulation of PD-L1 in PeSCC included both extrinsic and intrinsic mechanisms. These findings indicated that the PD-1/PD-L1 axis might be a potential therapeutic target for patients with penile squamous cell carcinoma.
| S-EPMC5353932 | biostudies-literature
Project description:We have previously identified a human CD8+HLA-DR+ regulatory T cell subset with the ability to suppress proliferation of autologous PBMCs responder cells through cell contact and CTLA-4 co-inhibitory molecule. The present study characterizes the complete phenotype of CD8+HLA-DR+ Treg cells which showed great similarities with classical CD4+ cells expressing forkhead box P3 (FOXP3). The shared features included the expression of programmed cell death protein 1 (PD-1), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), C-C chemokine receptor type 4 and 5 (CCR4 and CCR5), low expression of CD127, and a memory and effector-like phenotype. CD8+HLA-DR+ Treg-induced suppression on CD8+ responder T cells was abrogated by an anti-PD1 neutralizing antibody. Anti-PD-1 did not abrogate the suppressor effect induced on responder CD4+ T cells. In addition, CD8+HLA-DR+ Treg induced a preferential death on responder CD8+ T cells. This effect was not reversed by PD-1 neutralization. After activation, most CD8+HLA-DR+ Treg acquire programmed death-ligand 1 (PD-L1) expression. Interestingly, PD-L1 may induce apoptosis through CD80 expressed on activated CD8+ responder T cells. After PBMCs stimulation, CD8+HLA-DR+ Treg cells showed an increased frequency of IFN-? and TNF? positive cells and higher degranulation. These data strongly argue against CD8+HLA-DR+ Treg being exhausted cells. Overall, the data presented in this study indicate that CD8+HLA-DR+ Treg and CD4+FOXP3+ Treg share phenotypic and functional features, which may provide cues to similar involvements in the control of antitumor immune responses and autoimmunity.
| S-EPMC6281883 | biostudies-literature
Project description:BackgroundThis study sought to depict the genomic landscape of patients with surgically resected lung squamous cell carcinoma (LUSC) and its relationship with clinical outcome indicators.MethodsWe retrospectively collected the clinical data of 180 patients from the electronic medical records and applied targeted sequencing and immunohistochemistry (IHC) to depict the genomic landscape, including the tumor mutation burden (TMB), programmed cell death-ligand 1 (PD-L1), and cluster of differentiation CD8+ tumor-infiltrating lymphocytes (CD8+ TILs). And comparative analysis and survival analysis of these parameters were conducted to find prognostic factors for clinical outcome.ResultsPD-L1+ tumor cells were observed in 75 (41.7%) of the patients, the median rate of CD8+ TILs was 11.5 [4, 24], and the median TMB was 9.4 (7.5-13.7) mutations per megabase (mut/Mb). Patched receptor 1 (PTCH1) gene mutation frequency was significantly associated with CD8+ TILs density (12% vs. 1%; P=0.024). High PD-L1 expression and CD8+ TILs+ were significantly associated with longer disease-free survival (DFS), and a further subgroup analysis revealed that both were significantly correlated with the DFS of stage I/II patients but not stage III patients.ConclusionsThe results suggest that only PTCH1 gene mutation frequency was correlated with CD8+ TILs density. Additionally, intense CD8+ TILs density and high PD-L1 expression were found to be associated with longer DFS. Our findings provide insights into the precise treatment strategy for surgically resected LUSC patients.
| S-EPMC9264043 | biostudies-literature
Project description:Even with the advance of diagnosis and the treatment, the 5-year survival rate for esophageal cancer patients is still poor. The checkpoint protein inhibition provides another choice to improve the survival. The expression of the programmed death ligand-1 (PD-L1) was reported but the clinical relevance remained inconsistent in esophageal cancer. Besides, there were few references about the other ligand, programed death ligand-2 (PD-L2). In this study, we evaluated the expressions of PD-L1 and PD-L2 in patients with esophageal squamous cell carcinoma (ESCC) and assessed their clinical relevance.From 1996 to 2011, 150 patients undergone complete surgical resection for ESCC were enrolled. Clinical data were recorded. Expression of PD-L1 and PD-L2 on cytoplasm in paraffin embedded tumor samples were analyzed by immunohistochemistry staining and scored with a semi-quantitative method.Of the patients, 96 (64.0%) patients had PD-L1 overexpression and 63 (42.0%) had PD-L2 overexpression. There was a correlation between the expression of PD-L1 and PD-L2 (P<0.001). Patients without overexpression of PD-L1, pathological T1-2 and N0 status, pathological stage I-II and no post-operative adjuvant treatment had a better disease free survival (DFS). In multivariate analysis, PD-L1 expression and pathological stage were the independent prognostic factors for DFS. The expression of PD-L2 did not influence the DFS. Although not statistically significant, patients without overexpression of PD-L1 and PD-L2 seem to have a better overall survival (OS).The overexpression of PD-L1 on cytoplasm, not PD-L2, is an independent prognostic factor for DFS in patients with ESCC undergone esophagectomy. However, there is a trend which suggested that patients without overexpression of PD-L1 and PD-L2 had a better OS.
| S-EPMC6106043 | biostudies-literature