The Prognostic and Predicting Roles of Tumor-Infiltrating Lymphocytes in Breast Cancer: A Meta-Analysis

Ibrahim, Ezzeldin M.; Al‐Foheidi, Meteb; Al‐Μansour, Mubarak; Kazkaz, Ghieth A.; Yunus, Tahir E.

doi:10.2174/1876817201406010009

Cited by 5 publications

(4 citation statements)

References 43 publications

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“…Nonetheless, TNBCs and HER2+ BCs grow despite high CTL infiltration, a finding suggesting that their mere presence is not reflecting effective immune function. In the clinical outcome analysis, high CD8+ TILs were associated with significantly prolonged BCSS, DFS and DMFS either in the entire group or the HR-subgroup, but not in the HR+ patients, in accordance to published reports (25,34,43,51,55,56,59,65). Total CD8+ TILs, namely intraepithelial and stromal TILs, are also shown as a prognostic factor for better OS, DFS and BCSS, especially in TNBC (66,67).…”

Section: Discussionsupporting

confidence: 86%

A Standardized Evaluation Method for FOXP3+ Tregs and CD8+ T-cells in Breast Carcinoma: Association With Breast Carcinoma Subtypes, Stage and Prognosis

et al. 2019

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Background/Aim: The role of FOXP3+ Tregs and CD8+ T-cells in different stages and subtypes of breast carcinoma (BC) is yet to be fully defined, mainly because of methodological variations between studies. The aim of this study was to assess FOXP3+ and CD8+ intratumoral stromal TILs (sTILs) by a standardized method, in order to discern differences between the histological subtypes and BC stage and evaluate the applicability of the method. Patients and Methods: FOXP3+ and CD8+ sTILs were studied immunohistochemically in 207 BCs and counted on digital images, amounting to a standard stromal area of a 10×10 grid on ×40 magnification. The results were correlated with clinicopathological features and outcomes. Results: Tregs and CD8+ TILs were more abundant in HER2+ BCs (p=0.02, p=0.007, respectively), estrogen receptor (ER)-BCs (p<0.001, for both cell types), and triple-negative BCs (TNBCs) (p=0.01, p=0.006, respectively). Tregs and CD8+ TILs were associated with high grade (p<0.001 and p=0.002, respectively) and high Ki67 index (p<0.001, for both cell types). Lower CD8/FOXP3 ratio was associated with node metastases (p=0.007). Node metastases and advanced stage paralleled with decreased CD8+ sTILs (p=0. 023, p=0.019, respectively). In the entire group and in ER-BCs, CD8+ TILs were associated with favorable distant metastasis-free survival (p=0.021, p<0.001, respectively), disease-free survival (p=0.022, p<0.001, respectively) and breast cancer specific survival (BCSS) (p=0.022, p=0.005). In ER-BCs, Tregs were associated with favorable BCSS (p=0.02). Conclusion: Tregs and CD8+ TILs are higher in early-stage TNBCs and HER2+ BCs and diminish with progression to advanced stages. The findings provide support for immunotherapeutic manipulation of TILs, particularly in early stages of these BC subtypes. The evaluation methodology can be easily implemented for standardization of immunohistochemically-detected TILs.

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Section: Discussionsupporting

confidence: 86%

A Standardized Evaluation Method for FOXP3+ Tregs and CD8+ T-cells in Breast Carcinoma: Association With Breast Carcinoma Subtypes, Stage and Prognosis

et al. 2019

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“…Previous VTA studies analyzing the prognostic impact of stromal TILs across various cutoff points on TNBC have yielded promising results [3][4][5][6]8]. A meta-analysis by Ibrahim et al [42] also revealed that every 10% increment in TILs might lead to a 15À20% reduction in disease recurrence or mortality in TNBC patients. On the other hand, a cutoff point of 10% for the TIL fraction, which was used in the CTA algorithm developed by Amgad et al [39], did not have any significant impact on overall survival in the breast cancer subgroup.…”

Section: Cohortmentioning

confidence: 99%

A Computational Tumor-Infiltrating Lymphocyte Assessment Method Comparable with Visual Reporting Guidelines for Triple-Negative Breast Cancer

Sun

Chao

et al. 2021

EBioMedicine

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Background: Tumor-infiltrating lymphocytes (TILs) are clinically significant in triple-negative breast cancer (TNBC). Although a standardized methodology for visual TILs assessment (VTA) exists, it has several inherent limitations. We established a deep learning-based computational TIL assessment (CTA) method broadly following VTA guideline and compared it with VTA for TNBC to determine the prognostic value of the CTA and a reasonable CTA workflow for clinical practice. Methods: We trained three deep neural networks for nuclei segmentation, nuclei classification and necrosis classification to establish a CTA workflow. The automatic TIL (aTIL) score generated was compared with manual TIL (mTIL) scores provided by three pathologists in an Asian (n = 184) and a Caucasian (n = 117) TNBC cohort to evaluate scoring concordance and prognostic value. Findings: The intraclass correlations (ICCs) between aTILs and mTILs varied from 0.40 to 0.70 in two cohorts. Multivariate Cox proportional hazards analysis revealed that the aTIL score was associated with disease free survival (DFS) in both cohorts, as either a continuous [hazard ratio (HR)=0.96, 95% CI 0.94À0.99] or dichotomous variable (HR=0.29, 95% CI 0.12À0.72). A higher C-index was observed in a composite mTIL/aTIL threetier stratification model than in the dichotomous model, using either mTILs or aTILs alone. Interpretation: The current study provides a useful tool for stromal TIL assessment and prognosis evaluation for patients with TNBC. A workflow integrating both VTA and CTA may aid pathologists in performing risk management and decision-making tasks.

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“…However, the picture of how tumor‐invasive immune cells and receptor subtypes are related in breast cancer remains incomplete. Reviews summarizing the association of TIL infiltration with survival in breast tumors show that outcomes depend on how immune cells are measured, which cell types are included, and how they modify the pathogenesis in different subtypes 9,10 …”

Section: Introductionmentioning

confidence: 99%

“…Reviews summarizing the association of TIL infiltration with survival in breast tumors show that outcomes depend on how immune cells are measured, which cell types are included, and how they modify the pathogenesis in different subtypes. 9 , 10 …”

Section: Introductionmentioning

confidence: 99%

Immunophenotype‐associated gene signature in ductal breast tumors varies by receptor subtype, but the expression of individual signature genes remains consistent

Behring

Elkholy

et al. 2021

Cancer Medicine

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Background In silico deconvolution of invasive immune cell infiltration in bulk breast tumors helps characterize immunophenotype, expands treatment options, and influences survival endpoints. In this study, we identify the differential expression (DE) of the LM22 signature to classify immune‐rich and ‐poor breast tumors and evaluate immune infiltration by receptor subtype and lymph node metastasis. Methods Using publicly available data, we applied the CIBERSORT algorithm to estimate immune cells infiltrating the tumor into immune‐rich and immune‐poor groups. We then tested the association of receptor subtype and nodal status with immune‐rich/poor phenotype. We used DE to test individual signature genes and over‐representation analysis for related pathways. Results CCL19 and CXCL9 expression differed between rich/poor signature groups regardless of subtype. Overexpression of CHI3L2 and FES was observed in triple negative breast cancers (TNBCs) relative to other subtypes in immune‐rich tumors. Non‐signature genes, LYZ, C1QB, CORO1A, EVI2B, GBP1, PSMB9, and CD52 were consistently overexpressed in immune‐rich tumors, and SCUBE2 and GRIA2 were associated with immune‐poor tumors. Immune‐rich tumors had significant upregulation of genes/pathways while none were identified in immune‐poor tumors. Conclusions Overall, the proportion of immune‐rich/poor tumors differed by subtype; however, a subset of 10 LM22 genes that marked immune‐rich status remained the same across subtype. Non‐LM22 genes differentially expressed between the phenotypes suggest that the biologic processes responsible for immune‐poor phenotype are not yet well characterized.

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The Prognostic and Predicting Roles of Tumor-Infiltrating Lymphocytes in Breast Cancer: A Meta-Analysis

Abstract: Background:The relationship between lymphocyte infiltrates (LIs) and breast cancer outcome remains controversial. We performed this meta-analysis to elucidate the relationship.

Cited by 5 publications

References 43 publications

A Standardized Evaluation Method for FOXP3+ Tregs and CD8+ T-cells in Breast Carcinoma: Association With Breast Carcinoma Subtypes, Stage and Prognosis

A Standardized Evaluation Method for FOXP3+ Tregs and CD8+ T-cells in Breast Carcinoma: Association With Breast Carcinoma Subtypes, Stage and Prognosis

A Computational Tumor-Infiltrating Lymphocyte Assessment Method Comparable with Visual Reporting Guidelines for Triple-Negative Breast Cancer

Immunophenotype‐associated gene signature in ductal breast tumors varies by receptor subtype, but the expression of individual signature genes remains consistent

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