Clinical Significance of Tumor Infiltrating Lymphocytes in Association with Hormone Receptor Expression Patterns in Epithelial Ovarian Cancer.
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ABSTRACT:
SUBMITTER: Han GH
PROVIDER: S-EPMC8198528 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The accumulation of tumor infiltrating lymphocytes (TILs) in ovarian cancer is prognostic for increased survival while increases in immunosuppressive regulatory T-cells (Tregs) are associated with poor outcomes. Approaches that bolster tumor-reactive TILs may limit tumor progression. However, identifying tumor-reactive TILs in ovarian cancer has been challenging, though adoptive TIL therapy in patients has been encouraging. Other forms of TIL immunomodulation remain under investigation including Treg depletion, antibody-based checkpoint modification, activation and amplification using dendritic cells, antigen presenting cells or IL-2 cytokine culture, adjuvant cytokine injections, and gene-engineered T-cells. Many approaches to TIL manipulation inhibit ovarian cancer progression in preclinical or clinical studies as monotherapy. Here, we review the impact of TILs in ovarian cancer and attempts to mobilize TILs to halt tumor progression. We conclude that effective TIL therapy for ovarian cancer is at the brink of translation and optimal TIL activity may require combined methodologies to deliver clinically-relevant treatment.
| S-EPMC4622931 | biostudies-literature
Project description:There is evidence that some ovarian tumours evoke an immune response, which can be assessed by tumour infiltrating lymphocytes (TILs). To facilitate adoption of TILs as a clinical biomarker, a standardised method for their H&E visual evaluation has been validated in breast cancer.We sought to investigate the prognostic significance of TILs in a study of 953 invasive epithelial ovarian cancer tumour samples, both primary and metastatic, from 707 patients from the prospective population-based SEARCH study. TILs were analysed using a standardised method based on H&E staining producing a percentage score for stromal and intratumoral compartments. We used Cox regression to estimate hazard ratios of the association between TILs and survival.The extent of stromal and intra-tumoral TILs were correlated in the primary tumours (n = 679, Spearman's rank correlation = 0.60, P < 0.001) with a similar correlation in secondary tumours (n = 224, Spearman's rank correlation = 0.62, P < 0.001). There was a weak correlation between stromal TIL levels in primary and secondary tumour samples (Spearman's rank correlation = 0.29, P < 0.001) and intra-tumoral TIL levels in primary and secondary tumour samples (Spearman's rank correlation = 0.19, P = 0.0094). The extent of stromal TILs differed between histotypes (Pearson chi2 (12d.f.) 54.1, P < 0.0001) with higher levels of stromal infiltration in the high-grade serous and endometriod cases. A significant association was observed for higher intratumoral TIL levels and a favourable prognosis (HR 0.74 95% CI 0.55-1.00 p = 0.047).This study is the largest collection of epithelial ovarian tumour samples evaluated for TILs. We have shown that stromal and intratumoral TIL levels are correlated and that their levels correlate with clinical variables such as tumour histological subtype. We have also shown that increased levels of both intratumoral and stromal TILs are associated with a better prognosis; however, this is only statistically significant for intratumoral TILs. This study suggests that a clinically useful immune prognostic indicator in epithelial ovarian cancer could be developed using this technique.
| S-EPMC5607562 | biostudies-literature
Project description:ObjectiveTo predict the prognosis of cervical cancer, we constructed a novel model with 5 specific cell types and identified a potential biomarker.MethodsWe employed CIBERSORT and xCell method to evaluate the abundances of 23 cells types in tumor microenvironment. Five specific cell types were filtrated to determine different immunotypes by applying least absolute shrinkage and selection operator (LASSO) Cox regression method. The expression of immune checkpoints (ICPs) and effectors were validated by immunohistochemistry. Correlation analysis was performed to examine the relevance between PIK3CA mutational status and ICPs.ResultsUnsupervised clustering of patients on the basis of tumor infiltrating lymphocytes and fibroblasts identified patients with shorter overall survival (OS) (hazard ratio [HR]=3.0729; 95% confidence interval [CI]=1.5103-6.2522; p=0.0118). An immunoscore (IS) signature consisting of 5 immune cell types infiltrating in tumor core (CD8T, activated NK cells, neutrophils, activated mast cells, macrophages) was constructed using LASSO Cox regression analysis. Receiver operating characteristic curves confirmed that the area under the curve of IS was significantly higher to that of International Federation of Gynecology and Obstetrics staging alone (0.637 vs. 0.55). Survival analysis revealed patients in high IS group exhibited a poorer OS (HR=3.0113; 95% CI=1.8746-4.8373; p<0.0001). The multivariate analysis indicated the IS was an independent prognostic factor. In addition, the lower IS related to higher expression of ICPs and neoantigen load.ConclusionsThe identification of IS in cervical cancer tissues could facilitate patient risk stratification and selection of immunotherapeutic responses, but more prospective studies are needed to assess its reliability.
| S-EPMC8039170 | biostudies-literature
Project description:BackgroundBreast cancer subtypes are known to have different metastatic recurrence sites. Distant metastases are often observed during the post-operative course in patients with human epidermal growth factor receptor 2 (HER2)-enriched breast cancer and triple-negative breast cancer, but are relatively rare in those with hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer. Tumor-infiltrating lymphocytes (TILs) serve as an index to monitor tumor immune microenvironment and may possibly predict the prognosis and therapeutic effect in breast cancer. This study aimed to investigate the correlation between TIL density and recurrence site in HR+/HER2- breast cancer.MethodsIn stages I-II of HR+/HER2- breast cancer patients who underwent surgery as the first treatment and received adjuvant endocrine therapy (except adjuvant chemotherapy), forty-two patients relapsed after surgery. TILs were evaluated using needle biopsy specimens for the diagnosis of breast cancer. Morphological assessment was conducted using conventional hematoxylin and eosin staining.ResultsSix patients had no TILs density. In them, local recurrence was significantly less (p = 0.022), while distant metastases were significantly more (p = 0.015) compared to those in patients with TIL density. Therefore, for the prediction of distant metastases in HR+/HER2- breast cancer without chemotherapy, TILs could be used as predictors in univariate analysis (p = 0.015, odds ratio [OR] = 0.127), although not as independent factors (p = 0.285, OR = 0.144).ConclusionsOur findings indicate that TILs may predict distant metastatic recurrence in stages I-II of HR+/HER2- breast cancer in patients who do not undergo chemotherapy.
| S-EPMC8164786 | biostudies-literature
Project description:The prognostic value of tumor-infiltrating lymphocytes (TILs) in ovarian cancer is still in controversial. This study is aimed to assess the impact of different TIL subsets on the progression free survival (PFS)/disease free survival (DSS) and overall survival (OS)/disease specific survival (DSS) in ovarian cancer. A comprehensive literature search in PubMed, ISI Web of Science, and Medline was performed to identify relevant studies evaluating the prognostic value of TILs in ovarian cancer. Reviews of each study were conducted and data were extracted. The main outcomes analyzed were PFS/DFS and OS/DSS. A total of 21 eligible studies enrolling 2903 ovarian cancer patients were included for the meta-analysis. The overall analysis revealed that intraepithelial CD3+ and CD8+ TILs were strongly associated with improved PFS/DFS (HR=0.53, for CD3+ TILs; and HR=0.50, for CD8+ TILs). Intraepithelial CD8+/Foxp3+ ratios appeared to be associated with improved PFS, though without reaching statistical significance (HR=0.73). Moreover, intraepithelial CD3+, CD8+, and CD103+ TILs were clearly associated with increased OS/DSS (HR=0.50, for CD3+ TILs; HR=0.62, for CD8+ TILs; HR=0.54, for CD103+ TILs). However, intraepithelial FoxP3+ TILs, CD8+/FoxP3+ ratios, CD8+/CD4+ ratios, and stromal TILs had no impact on the OS/DSS (HR=0.98, for FoxP3+ TILs; HR=0.69, for CD8+/FoxP3+ ratios; HR=0.48, for CD8+/CD4+ ratios; HR=0.82, for stromal TILs). In conclusion, the present meta-analysis supports the hypothesis that intraepithelial TILs are predictive biomarkers for the prognosis of ovarian cancer patients. Future randomized studies are needed to verify these observations.
| S-EPMC5362510 | biostudies-literature
Project description:Importance:Cytotoxic CD8+ tumor-infiltrating lymphocytes (TILs) participate in immune control of epithelial ovarian cancer; however, little is known about prognostic patterns of CD8+ TILs by histotype and in relation to other clinical factors. Objective:To define the prognostic role of CD8+ TILs in epithelial ovarian cancer. Design, Setting, and Participants:This was a multicenter observational, prospective survival cohort study of the Ovarian Tumor Tissue Analysis Consortium. More than 5500 patients, including 3196 with high-grade serous ovarian carcinomas (HGSOCs), were followed prospectively for over 24?650 person-years. Exposures:Following immunohistochemical analysis, CD8+ TILs were identified within the epithelial components of tumor islets. Patients were grouped based on the estimated number of CD8+ TILs per high-powered field: negative (none), low (1-2), moderate (3-19), and high (?20). CD8+ TILs in a subset of patients were also assessed in a quantitative, uncategorized manner, and the functional form of associations with survival was assessed using penalized B-splines. Main Outcomes and Measures:Overall survival time. Results:The final sample included 5577 women; mean age at diagnosis was 58.4 years (median, 58.2 years). Among the 5 major invasive histotypes, HGSOCs showed the most infiltration. CD8+ TILs in HGSOCs were significantly associated with longer overall survival; median survival was 2.8 years for patients with no CD8+ TILs and 3.0 years, 3.8 years, and 5.1 years for patients with low, moderate, or high levels of CD8+ TILs, respectively (P value for trend?=?4.2?×?10?16). A survival benefit was also observed among women with endometrioid and mucinous carcinomas, but not for those with the other histotypes. Among HGSOCs, CD8+ TILs were favorable regardless of extent of residual disease following cytoreduction, known standard treatment, and germline BRCA1 pathogenic mutation, but were not prognostic for BRCA2 mutation carriers. Evaluation of uncategorized CD8+ TIL counts showed a near-log-linear functional form. Conclusions and Relevance:This study demonstrates the histotype-specific nature of immune infiltration and provides definitive evidence for a dose-response relationship between CD8+ TILs and HGSOC survival. That the extent of infiltration is prognostic, not merely its presence or absence, suggests that understanding factors that drive infiltration will be the key to unraveling outcome heterogeneity in this cancer.
| S-EPMC5744673 | biostudies-literature
Project description:Thymic epithelial tumors (TETs) are rare malignant mediastinal tumors that are difficult to diagnose and treat. The programmed death 1 (PD-1) receptor and its ligand (PD-L1) are expressed in various malignant tumors and have emerged as potential immunotherapeutic targets. However, the immunobiology of TETs is poorly understood. We evaluated PD-L1 expression and the presence of tumor-infiltrating lymphocytes (CD8 and CD3 expression) in surgical TET specimens from 39 patients via immunohistochemistry and determined their relation to clinicopathological parameters. Cases with membranous reactivity of the PD-L1 antibody in ?1% of tumor cells were considered positive. Positive PD-L1 expression was observed in 53.9% of cases. Histologically, PD-L1 expression was positive in 2/6 type A, 2/6 type AB, 3/9 type B1, 4/4 type B2, 5/6 type B3, and 5/8 type C TET cases. Thus, the number of cases with PD-L1 expression and the percent expression of PD-L1 were significantly higher in more aggressive thymomas (type B2 or B3). CD3+ and CD8+ tumor-infiltrating lymphocytes were diffusely and abundantly distributed in all cases. These data suggest that a PD-1/PD-L1 blockade is a promising treatment for TETs, with more beneficial treatment effects for aggressive thymomas such as type B2 or B3.
| S-EPMC6912585 | biostudies-literature
Project description:Neoadjuvant therapy for locally advanced rectal cancer is becoming increasingly common. However, biomarkers predicting the response to neoadjuvant therapy have not been established. Tumor-infiltrating lymphocytes (TILs) have a crucial effect on tumor progression and survival outcome as the primary host immune response, and an antitumor immune effect has been reported to contribute to the response to radiotherapy and chemotherapy. We investigated the significance of TILs before and after neoadjuvant treatment and the change in the density of those TILs. Sixty-four patients who underwent radical resection after neoadjuvant treatment for locally advanced rectal cancer were enrolled. The number of TIL subsets was examined using immunohistochemical staining of pretreatment biopsy samples and post-treatment resected specimens. In both the neoadjuvant chemotherapy cohort and the neoadjuvant chemoradiotherapy cohort, a low density of CD8+ TILs in pretreatment biopsy samples was associated with a poor response, and a low density of CD8+ TILs in post-treatment resected specimens was similarly associated with a poor response. In the neoadjuvant chemoradiotherapy cohort, the density of CD8+ TILs in post-treatment resected specimens was significantly increased compared with that in pretreatment biopsy samples. We concluded that T lymphocyte-mediated immune reactions play an important role in tumor response to neoadjuvant treatment for rectal cancer, and the evaluation of TILs in pretreatment biopsy samples might be a predictor of the clinical effectiveness of neoadjuvant treatment. Furthermore, neoadjuvant therapy, especially chemoradiotherapy, could induce the activation of the local immune status.
| S-EPMC5891199 | biostudies-literature
Project description:Tumor infiltrating lymphocytes (TILs) play a significant role in the tumor microenvironment in high-grade serous ovarian cancer (HGSOC). To better understand the interactions and functions of TILs in HGSOC progression, we performed proteogenomic profiling of TILs in 65 tumors collected from 12 HGSOC patients.
2024-03-15 | PXD045710 | Pride
Project description:Adoptive cell therapy using tumor-infiltrating lymphocytes (TIL) is arguably the most effective treatment for patients with metastatic melanoma. With higher response rates than ipilimumab or IL-2, and longer durations of response than vemurafenib, TIL therapy carries the potential to transform current outcomes in melanoma, while also defining the way cell-based immunotherapy gets incorporated into mainstream cancer treatment. This paper will review the current state of TIL therapy in melanoma, the strategies to improve its efficacy, the current obstacles, and future directions to expand the availability of TIL to the general patient population.
| S-EPMC3462483 | biostudies-literature