CD8 tumor-infiltrating lymphocytes are predictive of survival in muscle-invasive urothelial carcinoma.
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SUBMITTER: Sharma P
PROVIDER: S-EPMC1820692 | biostudies-literature | 2007 Mar
REPOSITORIES: biostudies-literature
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Tattoo related pyoderma/ectyma gangrenous as presenting feature of relapsed acute myeloid leukaemia: an exceptionally rare observation.
Tendas Andrea A Niscola Pasquale P Barbati Rosanna R Abruzzese Elisabetta E Cuppelli Luca L Giovannini Marco M Scaramucci Laura L Fratoni Stefano S Ales Micaela M Neri Benedetta B Morino Luciana L Dentamaro Teresa T De Fabritiis Paolo P
Injury 20110501 5
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Project description:IntroductionRandomized controlled trials of platinum-based neoadjuvant chemotherapy (NAC) for bladder cancer have shown that patients who achieve a pathologic response to NAC exhibit 5 y survival rates of approximately 80-90% while NAC resistant (NR) cases exhibit 5 y survival rates of approximately 30-40%. These findings highlight the need to predict who will benefit from conventional NAC and the need for plausible alternatives.MethodsThe pre-treatment biopsy tissues from a cohort of 41 patients with muscle invasive bladder who were treated with NAC were incorporated in tissue microarray and immunohistochemistry for PD-L1, CD8, and FOXP3 was performed. Percentage of PD-L1 positive tumor cells was measured. Tumor-infiltrating lymphocytes (TIL) densities, along with CD8 and Treg-specific TILs, were measured.ResultsTIL density was strongly correlated with tumor PD-L1 expression, consistent with the mechanism of adaptive immune resistance in bladder cancer. Tumor cell PD-L1 expression was not a significant predictor of response. Neither was the CD8 nor Treg TIL density associated with response. Intriguingly though, the ratio of CD8 to Treg TIL densities was strongly associated with response (p = 0.0003), supporting the hypothesis that the immune system plays a role in the response of bladder cancer to chemotherapy.DiscussionTo our knowledge, this is the first report in bladder cancer showing that the CD8 to Treg TIL density in the pre-treatment tissues is predictive for conventional NAC response. These findings warrant further investigations to both better characterize this association in larger cohorts and begin to elucidate the underlying mechanism(s) of this phenomenon.
| S-EPMC4910705 | biostudies-literature
Project description:(1) Purpose: Although assessment of tumor-infiltrating lymphocytes (TILs) has been acknowledged to have important predictive prognostic value in muscle-invasive bladder cancer (MIBC), it is limited by inter- and intra-observer variability, hampering widespread clinical application. We aimed to evaluate the prognostic value of quantitative TILs score based on a machine learning (ML) algorithm to identify MIBC patients who might benefit from immunotherapy or the de-escalation of therapy. (2) Methods: We constructed an artificial neural network classifier for tumor cells, lymphocytes, stromal cells, and "ignore" cells from hematoxylin-and-eosin-stained slide images using the QuPath open source software. We defined four unique TILs variables based on ML to analyze TILs measurements. Pathological slide images from 133 MIBC patients were retrospectively collected as the discovery set to determine the optimal association of ML-read TILs variables with patient survival outcomes. For validation, we evaluated an independent external validation set consisting of 247 MIBC patients. (3) Results: We found that all four TILs variables had significant prognostic associations with survival outcomes in MIBC patients (p < 0.001 for all comparisons), with higher TILs score being associated with better prognosis. Univariate and multivariate Cox regression analyses demonstrated that electronic TILs (eTILs) variables were independently associated with overall survival after adjustment for clinicopathological factors including age, sex, and pathological stage (p < 0.001 for all analyses). Results analyzed in different subgroups showed that the eTILs variable was a strong prognostic factor that was not redundant with pre-existing clinicopathological features (p < 0.05 for all analyses). (4) Conclusion: ML-driven cell classifier-defined TILs variables were robust and independent prognostic factors in two independent cohorts of MIBC patients. eTILs have the potential to identify a subset of high-risk stage II or stage III-IV MIBC patients who might benefit from adjuvant immunotherapy.
| S-EPMC9739988 | biostudies-literature
Project description:Novel systemic treatments for hepatocellular carcinoma (HCC) are strongly needed. Immunotherapy is a promising strategy that can induce specific antitumor immune responses. Understanding the mechanisms of immune resistance by HCC is crucial for development of suitable immunotherapeutics. We used immunohistochemistry on tissue-microarrays to examine the co-expression of the immune inhibiting molecules PD-L1, Galectin-9, HVEM and IDO, as well as tumor CD8+ lymphocyte infiltration in HCC, in two independent cohorts of patients. We found that at least some expression in tumor cells was seen in 97% of cases for HVEM, 83% for PD-L1, 79% for Gal-9 and 66% for IDO. In the discovery cohort (n = 94), we found that lack of, or low, tumor expression of PD-L1 (p < 0.001), Galectin-9 (p < 0.001) and HVEM (p < 0.001), and low CD8+TIL count (p = 0.016), were associated with poor HCC-specific survival. PD-L1, Galectin-9 and CD8+TIL count were predictive of HCC-specific survival independent of baseline clinicopathologic characteristics and the combination of these markers was a powerful predictor of HCC-specific survival (HR 0.29; p <0.001). These results were confirmed in the validation cohort (n = 60). We show that low expression levels of PD-L1 and Gal-9 in combination with low CD8+TIL count predict extremely poor HCC-specific survival and it requires a change in two of these parameters to significantly improve prognosis. In conclusion, intra-tumoral expression of these immune inhibiting molecules was observed in the majority of HCC patients. Low expression of PD-L1 and Galectin-9 and low CD8+TIL count are associated with poor HCC-specific survival. Combining immune biomarkers leads to superior predictors of HCC mortality.
| S-EPMC5353918 | biostudies-literature
Project description:Drugs blocking programmed death ligand-1 (PD-L1) have shown unprecedented activity in metastatic and unresectable bladder cancer. The purpose of the present study was to investigate the expression, clinical significance and association of PD-L1 with tumor-infiltrating lymphocytes (TIL) in resectable urothelial cell carcinoma of the bladder (UCB). In this retrospective study, 248 UCB patients who received radical cystectomy or transurethral resection were examined. Immunohistochemistry was used to evaluate PD-L1 expression and stromal CD8+ TIL, Th1 orientation T cell (T-bet+ ) and PD-1+ TIL densities within the intratumoral regions and associated stromal regions. Of the 248 specimens, 23% showed PD-L1 expression in tumor cells and 55% in tumor-infiltrating immune cells. CD8+ TIL, T-bet+ TIL and PD-1+ TIL were distributed throughout the tumor tissues and were more frequently distributed in stromal regions than in intratumoral regions. PD-L1+ tumor cells and PD-L1+ immune cells were positively associated with aggressive clinical features (all P < .05). Both PD-L1+ tumor cells and PD-L1+ immune cells were associated with poorer recurrence-free and overall survival (all P < .05). Multivariate analysis showed that PD-L1+ immune cells were an independent prognostic factor for overall (P = .001) and recurrence-free survival (P = .024). Notably, high stromal CD8+ TIL and PD-1+ TIL density were associated with poorer overall survival (P = .031 and P = .001, respectively). In the stroma, CD8+ TIL density has strong positive association with PD-L1+ immune cells and PD-1+ TIL density (all P < .0001). These results suggested that an exhausted immune state occurred in the tumor stroma in UCB. Further clinical development of immune-checkpoint inhibitors may be effective for resectable patients with UCB.
| S-EPMC6361576 | biostudies-literature
Project description:Tumor-infiltrating lymphocytes (TILs) are associated with better clinical outcomes in many tumors. TILs represent a cell-mediated immune response against the carcinoma. CD8+ TILs are a crucial component of cell-mediated immunity. The significance of CD8+ TILs has not been reported respectively in organ- and non-organ-confined urothelial carcinoma (UC) of the bladder. We explored the prognostic value of CD8+ TILs in the two groups. The presence of CD8+ TILs was assessed by immunohistochemical staining of whole tissue sections from 75 organ and 51 non-organ-confined disease patients with long-term follow-up, and its correlation with clinicopathological features and overall survival (OS) was determined. The CD8+ TIL immunohistochemical staining score was 0 (<1%), 1 (≥1%), 2 (≥5%), or 3 (≥10%) based on the percentage of positively stained cells out of total cells. A patient was considered CD8 negative if the score was 0. There were no associations between CD8+ TILs and age, sex, nuclear grade, and adjuvant or neoadjuvant chemotherapy in organ- and non-organ-confined disease. The presence of CD8+ TILs was seen more frequently in pTa-1 than pT2 stage (p = 0.033) in organ-confined disease. No associations between CD8+ TILs and pT stage, pN stage were found in non-organ-confined disease. CD8+ TILs were associated with better OS (log-rank test, P = 0.036) in non-organ-confined disease, but with poorer OS (log-rank test, P = 0.040) in organ-confined disease by the Kaplan-Meier method. In multivariate analysis, CD8+ TILs were an independent favorable prognostic factor in non-organ-confined disease, but were an independent unfavorable prognostic factor in organ-confined disease. These results suggest that CD8+ TILs have clinically significant anti-tumor activity in non-organ-confined disease, but may have pro-tumor activity in organ-confined disease. Therefore, we should be cautious if CD8+ TILs are aimed to be exploited in the treatment of bladder cancer.
| S-EPMC5642242 | biostudies-literature
Project description:BackgroundTumor-infiltrating lymphocytes (TIL) in colorectal tumor tissue are significantly correlated with a favorable prognosis, such as CD8+ lymphocytes, which are also called tumor-reactive lymphocytes. However, not all tumor-infiltrating T cells confer benefit to patients. Therefore, it is of substantial benefit to identify a biomarker to demarcate these tumor-reactive lymphocytes.MethodsWe investigated whether ITGAE could be used to discriminate reactive CD8+ lymphocytes in colorectal cancer (CRC). TCGA colorectal cancer data sets (n1 = 492, n2 = 386) and FUSCC set (n3 = 276) were used in this study. Further phenotyping of ITGAE+ cells and the mechanistic basis were investigated.FindingsIn the training and testing sets from TCGA, ITGAE expression, which is strongly correlated with cytotoxic T cell markers (CD8/CD3/PD1), independently predicted longer disease-free survival (DFS) and overall survival (OS). In line with this, the association between ITGAE+ lymphocytes and survival has been confirmed in the FUSCC cohort for validation (P = .026). ITGAE + cells in the series always co-stained with CD8 were preferentially located in the tumor. Interestingly, ITGAE+ lymphocytes tended to associate with the epithelial-mesenchymal transition (EMT) with decreased Snail and increased E-cadherin expression accompanied. Finally, gene set enrichment analysis showed that immune activation was significantly enriched in the high ITGAE+ TIL group, accompanied by enriched EMT-related pathways.InterpretationBecause of the specified expression of tumor-reactive CD8+ T-cells, ITGAE may be a promising biomarker for the rapid identification of immune infiltration in CRC.
| S-EPMC6154785 | biostudies-literature
Project description:BackgroundMerkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine carcinoma of the skin. As the clinical course can be variable, prognostic markers are needed to better stratify patients. Prior literature, composed of small series with limited sample size, has demonstrated that tumor-infiltrating lymphocytes (TILs) are an important prognostic marker in MCC. To validate these findings on a population level, we sought to analyze and report the prognostic value of TILs in a large national data set.Materials and methodsA retrospective observational cohort study was conducted of patients with nonmetastatic MCC from 2010 to 2015 using the National Cancer Database. Individual variables trending toward significance using a univariable analysis were included in a multivariable Cox proportional hazards model to assess their independent effect on overall survival (OS). TILs were subclassified into none, nonbrisk, and brisk and the survival analysis was performed. Propensity score-weighted multivariable analysis (PS MVA) was performed to adjust for additional confounding.ResultsA total of 2,182 patients met inclusion criteria: 611 (28.0%) were identified as having TILs present, and 1,571 (72.0%) had TILs absent in the tumor. On MVA, subdivision of TIL status into nonbrisk (hazard ratio [HR], 0.750; 95% confidence interval [CI], 0.602-0.933) and brisk (HR, 0.499; 95% CI, 0.338-0.735) was associated with incrementally improved OS compared with no TILs. The association of nonbrisk and brisk TILs with improved OS was retained on PS MVA (Nonbrisk: HR, 0.720; 95% CI, 0.550-0.944; Brisk: HR, 0.483; 95% CI, 0.286-0.814).ConclusionThe presence of nonbrisk and brisk TILs is associated with incrementally improved OS in patients with nonmetastatic MCC in a large national data set. This pathologic feature can aid with risk stratification, estimation of prognosis, and, importantly, decision-making with respect to treatment intensification in high-risk patients.Implications for practiceMerkel cell carcinoma (MCC) is an aggressive neuroendocrine cutaneous malignancy with variable clinical course. Prognostic markers are needed to better risk stratify patients. We present the largest retrospective observational cohort study of patients with nonmetastatic MCC using the National Cancer Database. Our analysis demonstrates an association between increasing degrees of tumor-infiltrating lymphocytes and incrementally improved survival. These conclusions improve pathologic risk stratification, and decision-making with respect to treatment intensification. Intensification may include adjuvant radiation therapy to the primary site after wide excision despite small tumor size, to the nodal basin in sentinel lymph node-negative patients, or offering closer follow-up.
| S-EPMC7794178 | biostudies-literature
Project description:The impact of tumor infiltrating lymphocytes (TILs) on survival was confirmed in various cancer types. Our study aims to investigate the prognostic role of TILs on survival in patients with metastatic urothelial carcinoma (mUC) receiving platinum based chemotherapy. Patients who were diagnosed to have pathologically proved mUC between 1997 and 2016 and received palliative chemotherapy with platinum based regimen were recruited into our study. Kaplan-Meier curves and Cox regression analysis were constructed for overall survival (OS). A total of 259 mUC patients were enrolled into our study with median age 63 years and median follow-up visit 13.5 months. Of these patients, 179 (69%) had intense TILs and 80 (31%) had non-intense TILs. The median OS were 15.7 vs. 6.7 months (P?=?<?0.001) for patients with intense TILs and non-intense TILs, respectively. Subgroup analysis showed that TILs was both prognostically significant no matter for urothelial carcinoma of bladder and upper tract urothelial carcinoma. Multivariate analysis showed that TILs were strongly prognostic factors related to OS. Our study suggested mUC patients with intense TILs were independently associated with survival. Based on our study, TILs is clinically useful for outcomes anticipation and risk stratification, as well as patients counseling.
| S-EPMC5945658 | biostudies-literature
Project description:Purpose:The presence of CD8+ tumor-infiltrating lymphocytes (TILs) has been reported to be associated with treatment outcomes in many types of solid tumors. However, the results vary due to the various methods of visual estimation and subjective interpretation. The current study is the first to use digital image analyses to evaluate the density of CD8+/CD3+ TILs in tongue squamous cell carcinoma (TSCC). Patients and Methods:From 2005 to 2015, a cohort of 258 TSCC patients were consecutively enrolled in this study. After immunohistochemistry on representative sections, the density of CD8+/CD3+ TILs at tumor invasive margins was evaluated by digital image analysis. The subjects were stratified by the median values of CD3+ cell density, CD8+ cell density, CD8/CD3, and scores (0, 1, and 2) to demonstrate the association with various clinicopathological manifestations. Results:Low CD8+ TIL counts were associated with advanced tumor stages (p=0.034), and low CD8/CD3 ratios were associated with perineural invasion (p=0.043). Both parameters were also associated with increased tumor depths (p=0.034 and 0.004, respectively). Univariate analyses revealed that advanced tumor stages, perineural invasion, extranodal extension, tumor depth, lower CD8 counts, and lower scores (score 0 vs 2) were associated with poorer overall survival, and multivariate analysis further indicated that extranodal extension and low scores (score 0 vs 2) were both independent factors for overall survival (p < 0.0001 and p = 0.0369, respectively). Conclusion:The use of digital image analysis to assess CD8+ TILs at the invasive margins provides an objective indicator of prognoses including overall survival.
| S-EPMC7490039 | biostudies-literature
Project description:BACKGROUND:Because immune responses within the tumor microenvironment are important predictors of tumor biology, correlations of types of tumor infiltrating lymphocytes (TILs) with clinical outcomes were determined in 278 patients with head and neck squamous cell carcinoma (HNSCC). METHODS:Infiltrating levels of CD4 (helper T cells), CD8 (cytotoxic/suppressor T cells), FoxP3 (regulatory T cells), CD68 (myeloid-derived suppressor cells,) and CD1a (Langerhans) cells were measured in tissue microarrays (TMAs). Cox models tested associations with patient outcomes after adjusting for all known prognostic factors. Median follow-up was 36.6 months. RESULTS:Higher CD4 and CD8 TIL levels were associated with improved overall survival (OS; hazard ratio [HR]?=?0.77; 95% confidence interval [CI] ?=?0.65-0.93; p?=?.005 and HR?=?0.77; 95% CI?=?0.64-0.94; p?=?.008, respectively), and relapse-free survival (RFS; p?=?.03 and .05, respectively). After controlling for prognostic factors, higher CD4 levels predicted improved OS and disease-specific survival (DSS; p?=?.003 and p?=?.004, respectively). CONCLUSION:The findings suggest that TILs are a significant independent prognostic factor for HNSCC that differ by treatment. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1074-1084, 2016.
| S-EPMC4900934 | biostudies-literature