Quantifying Spatial Heterogeneity of Tumor-Infiltrating Lymphocytes to Predict Survival of Individual Cancer Patients.
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ABSTRACT:
SUBMITTER: Suwalska A
PROVIDER: S-EPMC9317291 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Checkpoint inhibitors targeting PD-(L)1 induce objective responses in 20% of patients with metastatic urothelial cancer (UC). CD8+ T cell infiltration has been proposed as a putative biomarker for response to checkpoint inhibitors. Nevertheless, data on spatial and temporal heterogeneity of tumor-infiltrating lymphocytes in advanced UC are lacking. The major aims of this study were to explore spatial heterogeneity for lymphocyte infiltration and to investigate how the immune landscape changes during the disease course. We performed multiplex immunohistochemistry to assess the density of intratumoral and stromal CD3+, CD8+, FoxP3+ and CD20+ immune cells in longitudinally collected samples of 49 UC patients. Within these samples, spatial heterogeneity for lymphocyte infiltration was observed. Regions the size of a 0.6 tissue microarray core (0.28 mm2) provided a representative sample in 60.6 to 71.6% of cases, depending on the cell type of interest. Regions of 3.30 mm2, the median tumor surface area in our biopsies, were representative in 58.8 to 73.8% of cases. Immune cell densities did not significantly differ between untreated primary tumors and metachronous distant metastases. Interestingly, CD3+, CD8+ and FoxP3+ T cell densities decreased during chemotherapy in two small cohorts of patients treated with neoadjuvant or palliative platinum-based chemotherapy. In conclusion, spatial heterogeneity in advanced UC challenges the use of immune cell infiltration in biopsies as biomarker for response prediction. Our data also suggests a decrease in tumor-infiltrating T cells during platinum-based chemotherapy.
| S-EPMC8761759 | biostudies-literature
Project description:Background: Tumor-infiltrating lymphocytes (TILs) play important roles in the prediction of prognosis and neoadjuvant therapy (NAT) efficacy in breast cancer (BRCA) patients, in this study, we identified clinicopathological factors related to BRCA TILs, then to construct and validate nomogram to predict high density of TILs. Methods: A total of 826 patients diagnosed with BRCA in Sun Yat-Sen University cancer center were enrolled in nomogram cohort. TILs were assessed using hematoxylin-eosin (H&E) staining by two pathologists. Complete clinical data were collected for analysis. Then the enrolled patients were split into a training set and validation set at a ratio of 8:2. and the backward multivariate binary logistic regression model was used to establish nomogram for predicting BRCA TILs, which were further evaluated and validated using the C-index, receiver operating characteristic (ROC) curves and calibration curves. Then another independent NAT cohort of 106 patients was established for verifying this nomogram in NAT efficacy prediction. Results: TILs were significantly correlated with body mass index (BMI), tumor differentiation, ER, PR, HER2 expression, Ki67, blood biochemical indicators including total bilirubin (TBIL), indirect bilirubin (IBIL), total protein (TP), Globulin (GLOB), inorganic phosphorus (IP), calcium (Ca). In which ER expression level [OR = 0.987, 95%CI (0.982-0.992), p < 0.001], IP [OR = 4.462, 95%CI (1.171∼17.289), p = 0.029], IBIL [OR = 0.906, 95%CI (0.845-0.966), p = 0.004] and TP [OR = 1.053, 95%CI (1.010-1.098, p = 0.016)] were independent predictors of TILs. Then nomogram was established, for which calibration curves (C-index = 0.759) and ROC curve (AUC = 0.759, 95%CI 0.717-0.801) in training sets, calibration curves (C-index = 0.708) and ROC curve (AUC = 0.708, 95%CI 0.617-0.800) in validation sets demonstrated great evaluation efficiency. Besides, independent NAT cohort verified this nomogram can distinguish patients with greater NAT efficacy (p = 0.041). Conclusion: The finds of clinicopathological factors associated with TILs could help clinicians to understand the tumor immunity of BRCA and improve treatment system for patients, and the established nomogram with high evaluation efficiency may be used as a complement tool for distinguishing patients with better NAT efficacy.
| S-EPMC8662984 | biostudies-literature
Project description:Intratumoral heterogeneity has been revealed in primary liver carcinoma (PLC). However, spatial heterogeneity of tumor-infiltrating lymphocytes (TILs), which reflects one dimension of a tumor's spatial heterogeneity, and the relationship between TIL diversity, local immune response and mutation burden remain unexplored in PLC. Therefore, we performed immune repertoire sequencing, gene expression profiling analysis and whole-exome sequencing in parallel on five regions of each tumor and on matched adjacent normal tissues and peripheral blood from five PLC patients. A significantly higher cumulative frequency of the top 250 most abundant TIL clones was observed in tumors than in peripheral blood. Besides, overlap rates of T cell receptor (TCR) repertoire for intratumor comparisons, significant higher than those for tumor-adjacent normal tissue comparisons and tumor-blood comparisons, which provide evidence for antigen-driven clonal expansion in PLC. Analysis of the percentage of ubiquitous TCR sequences, regional frequencies of each clone and TIL diversity suggested TIL clones varying between distinct regions of the same tumor, which indicated weak TCR repertoire similarity within a single tumor. Furthermore, correlation analysis revealed that TIL diversity significantly correlated with the expression of immune response genes rather than the mutation load. We conclude that intratumoural T-cell clones are spatially heterogeneous, which can lead to underestimate the immune profile of PLC from a single biopsy sample and may present challenge to adoptive cell therapy using autologous TILs. TIL diversity provides a reasonable explanation for the degree of immune response, implied TIL diversity can serve as a surrogate marker to monitor the effect of immunotherapy.
| S-EPMC5471016 | biostudies-literature
Project description:Tumor-infiltrating lymphocytes (TILs) have been established as a robust prognostic biomarker in breast cancer, with emerging utility in predicting treatment response in the adjuvant and neoadjuvant settings. In this study, the role of TILs in predicting overall survival and progression-free interval was evaluated in two independent cohorts of breast cancer from the Cancer Genome Atlas (TCGA BRCA) and the Carolina Breast Cancer Study (UNC CBCS). We utilized machine learning and computer vision algorithms to characterize TIL infiltrates in digital whole-slide images (WSIs) of breast cancer stained with hematoxylin and eosin (H&E). Multiple parameters were used to characterize the global abundance and spatial features of TIL infiltrates. Univariate and multivariate analyses show that large aggregates of peritumoral and intratumoral TILs (forests) were associated with longer survival, whereas the absence of intratumoral TILs (deserts) is associated with increased risk of recurrence. Patients with two or more high-risk spatial features were associated with significantly shorter progression-free interval (PFI). This study demonstrates the practical utility of Pathomics in evaluating the clinical significance of the abundance and spatial patterns of distribution of TIL infiltrates as important biomarkers in breast cancer.
| S-EPMC9105398 | biostudies-literature
Project description:Background: Compared with Caucasian Americans (CAs), African Americans (AAs) with colorectal cancer have poorer survival, especially younger-age patients. A robust lymphocytic reaction within colorectal cancers is strongly associated with better survival, but whether immune response impacts the disparity in colorectal cancer survival is unknown.Methods: The study population was comprised of 211 histologically confirmed colorectal cancers at the Medical University of South Carolina (Charleston, SC; 159 CAs and 52 AAs) diagnosed between Jan 01, 2000, and June 30, 2013. We constructed a lymphocyte score based on blinded pathologic assessment of the four different types of lymphocytic reactions. Cox proportional hazards regression was used to evaluate the association between the lymphocyte score and risk of death by race.Results: Colorectal cancers in AAs (vs. CAs) had a stronger lymphocytic reaction at diagnosis. A high lymphocyte score (vs. the lowest) was associated with better survival in AAs [HR 0.19; 95% confidence interval (CI), 0.04-0.99] and CAs (HR 0.47; 95% CI, 0.15-1.45). AAs with no lymphocytic reaction (vs. other categories) had poor survival HR 4.48 (1.58-12.7) whereas no difference was observed in CAs. The risk of death in AAs (vs. CA) was more pronounced in younger patients (HR 2.92; 95% CI, 1.18-7.22) compared with older (HR 1.20; 95% CI, 0.54-2.67), especially those with lymphocytic poor colorectal cancers.Conclusions: The lymphocytic reaction in tumor impacted the racial disparity in survival.Impact: Our results confirm the importance of the lymphocytic score on survival and highlight the need to fully characterize the immune environment of colorectal cancers by race. Cancer Epidemiol Biomarkers Prev; 27(7); 755-61. ©2018 AACR.
| S-EPMC6449046 | biostudies-other
Project description:Tumor-infiltrating lymphocytes (TILs) influence tumor prognosis and the chemotherapeutic response. Here, we quantified the clinical relevance of TILs, including the effect of TILs on lymphocyte subpopulations and assessed their consistency in breast cancer. We searched published literature from January 2000 to January 2016. The main parameters analyzed were pathological complete response (pCR) and survival outcome following chemotherapy in patients with breast cancer. Pooled odds ratio (OR) or relative risk (RR) values with 95% confidence intervals (CIs) were computed using random and fixed-effects models. Subgroup and heterogeneity analyses were also conducted. Twenty-three studies, which included 13,100 patients, met the inclusion criteria. The pooled results showed that TILs were associated with clinicopathological parameters of biologically aggressive phenotypes, such as high tumor grade or estrogen/progesterone receptor negativity, but they were not correlated with human epidermal growth factor receptor-2 expression. Moreover, a high TIL level was associated with a significantly improved pCR rate compared with a low TIL level (OR, 2.81; P < 0.001), particularly in the triple-negative breast cancer subtype (OR, 4.67; P < 0.001). An analysis of lymphocyte subpopulations showed that infiltration by CD8 lymphocytes, but not by CD4 lymphocytes and Foxp3 cells, was associated with a high pCR rate. Furthermore, a high TIL level was associated with significantly longer disease-free survival and overall survival. Our present meta-analysis indicates that an increased number of TILs predicted pCR to chemotherapy and improved survival. A high TIL level, characterized mainly by the infiltration of CD8 lymphocytes, is a strong predictive and prognostic factor.
| S-EPMC5190096 | biostudies-literature
Project description:Infiltration of tumor associated lymphocytes and count of its different phenotypes are potentially new independent predictor of prognosis in breast cancer. However, research related to it is less reported in breast cancer patients treated with anti-Her-2 therapy. Thus, we evaluated the relationship between survival and tumor infiltrating lymphocytes including its different phenotypes in tumors of such patients.Between 1999 and 2010, 98 patients diagnosed with primary breast cancer and treated with anti-Her-2 therapy at Sun-Yat-Sen University Cancer Center were included in the study. Biopsy specimens were collected post-operation but before chemotherapy. Tumor infiltrating lymphocytes as well as its FOXP3+, CD68+, IL-17+ phenotypes in both intratumoral and stromal sites and expression of FOXP3 in cancer cells were assessed.Median follow-up time of 98 patients was 83.3 months (range 7.4-201 months). It suggested that patients with high stromal infiltration of TILs, lower count of FOXP3+ Tregs and CD68+ M? in stromal site, and high expression of FOXP3 in cancer cells had longer survival of OS. In multivariate Cox regression analysis, high count of intratumoral CD68+ M? [HR: 2.70 (1.00-7.31); p=0.050] and high expression of FOXP3 in cancer cells [HR: 0.29 (0.09-0.91); p=0.034] were independent prognostic factors for overall survival.Tumor infiltrating lymphocytes as well as its FOXP3+, CD68+ phenotypes in stromal site, and expression of FOXP3 in cancer cells were significantly associated with OS, suggesting that they can be used as important pathological factor predicting prognosis of breast cancer patients treated with anti-Her-2 therapy.
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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
Project description:A high abundance of tumor-infiltrating lymphocytes (TILs) has a positive impact on the prognosis of patients with lung adenocarcinoma (LUAD). We aimed to develop and validate an artificial intelligence-driven pathological scoring system for assessing TILs on H&E-stained whole-slide images of LUAD. Deep learning-based methods were applied to calculate the densities of lymphocytes in cancer epithelium (DLCE) and cancer stroma (DLCS), and a risk score (WELL score) was built through linear weighting of DLCE and DLCS. Association between WELL score and patient outcome was explored in 793 patients with stage I-III LUAD in four cohorts. WELL score was an independent prognostic factor for overall survival and disease-free survival in the discovery cohort and validation cohorts. The prognostic prediction model-integrated WELL score demonstrated better discrimination performance than the clinicopathologic model in the four cohorts. This artificial intelligence-based workflow and scoring system could promote risk stratification for patients with resectable LUAD.
| S-EPMC9730047 | biostudies-literature
Project description:The clinical efficacy of immune checkpoint blockade has been recently demonstrated in a variety of cancer types. The aim of the present study was to characterize the expression profile of tumor-infiltrating lymphocytes (TILs) and programmed death-ligand 1 (PD-L1) in head and neck squamous carcinoma (HNSCC). A total of 63 patients with HNSCC were enrolled in the present study. CD3+ and CD4+ TILs and the expression of PD-L1 were detected by immunohistochemistry. PD-L1 mRNA levels were evaluated by reverse transcription-quantitative PCR analysis. The association of TILs and PD-L1 with patient clinicopathological characteristics was also assessed. CD3+ and CD4+ TILs were detected in 100% of the samples. CD3+ was the predominant subset of TILs. PD-L1 was expressed in 53 of 61 (86%) patients when a score of ≥1 on tumor cells was considered positive and in 28 patients (45.2%) when a score of >5 on tumor cells was considered positive. PD-L1 mRNA levels were determined to be significantly correlated with PD-L1 protein expression. Survival analysis demonstrated that high CD4+ TILs were associated with improved overall survival (OS) and disease-free survival (DFS), and furthermore, the association of high PD-L1 expression with unfavorable OS and DFS was statistically significant. Multivariate analysis identified CD4+ TILs and PD-L1 as prognostic markers for HNSCC. The results of the present study suggested that increased CD4+ TILs in HNSCC may be associated with improved outcomes, while high expression of PD-L1 may indicate unfavorable OS and DFS; thus, these factors may serve as predictors of the response to immune checkpoint therapy.
| S-EPMC8771311 | biostudies-literature