Tumor-Infiltrating Lymphocytes: A Promising Biomarker in Breast Cancer

B, Ingold Heppner; Loibl, Sibylle; Denkert, Carsten

doi:10.1159/000444357

Cited by 31 publications

(16 citation statements)

References 41 publications

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“…They are a population of cells comprising a mixture of cytotoxic T cells and helper T cells, as well as B cells, macrophages, natural killer cells, and dendritic cells. Whilst not discussed extensively in this manuscript, gene expression and flow cytometry profiles demonstrate that TIL quantity, as assessed semiquantitatively on a hematoxylin and eosin (H&E) stained slide, represents a surrogate for a pre-existing favourable host anti-tumor activated T cell response ( 4 , 5 ).…”

Section: Background: the Immune System And Tils In Breast Cancermentioning

confidence: 99%

Clinical Validity and Utility of Tumor-Infiltrating Lymphocytes in Routine Clinical Practice for Breast Cancer Patients: Current and Future Directions

et al. 2017

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The interest in tumor-infiltrating lymphocytes (TILs) as a prognostic biomarker in breast cancer has grown in recent years. Biomarkers must undergo comprehensive evaluation in terms of analytical validity, clinical validity and clinical utility before they can be accepted as part of clinical practice. The International Immuno-Oncology Biomarker Working Group has developed a practice guideline on scoring TILs in breast cancer in order to standardize TIL assessment. The prognostic value of TILs as a biomarker in early-stage breast cancer has been established by assessing tumor samples in thousands of patients from large prospective clinical trials of adjuvant therapy. There is a strong linear relationship between increase in TILs and improved disease-free survival for triple-negative and HER2-positive disease. Higher levels of TILs have also been associated with increased rates of pathological complete response to neoadjuvant therapy. TILs have potential clinical utility in breast cancer in a number of areas. These include prediction of responders to immune checkpoint blockade, identification of primary HER2-positive and triple-negative patients who have excellent prognoses and may thus be appropriate for treatment de-escalation, and potentially incorporation into a neoadjuvant endpoint which may be a better surrogate maker for drug development.

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Section: Background: the Immune System And Tils In Breast Cancermentioning

confidence: 99%

Clinical Validity and Utility of Tumor-Infiltrating Lymphocytes in Routine Clinical Practice for Breast Cancer Patients: Current and Future Directions

et al. 2017

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“…TILs are widely considered to be a key indicator of the immune interaction between host and tumor, and potentially effective predictive biomarkers of cancer immunogenicity, clinical outcome, response to immunotherapy and other antitumor treatments [ 5 , 6 , 7 , 8 , 9 , 10 , 11 ]. Although lymphocytic infiltrates have long been observed in breast cancer, only recent clinical trials have demonstrated the immunogenic nature of breast cancer and the potential role of host immunosurveillance in influencing tumor progression and treatment responses [ 5 , 8 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ]. B-cell infiltrates seem to play only a minor role in mammary tumor, where CD20+ cells are sporadically detected [ 25 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

Morphological Evaluation of Tumor-Infiltrating Lymphocytes (TILs) to Investigate Invasive Breast Cancer Immunogenicity, Reveal Lymphocytic Networks and Help Relapse Prediction: A Retrospective Study

Romagnoli

Wiedermann

Hübner

et al. 2017

IJMS

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Tumor-infiltrating lymphocytes (TILs) in breast cancer are a key representative of the tumor immune microenvironment and have been shown to provide prognostic and predictive biomarkers. The extent of lymphocytic infiltration in tumor tissues can be assessed by evaluating hematoxylin and eosin (H&E)-stained tumor sections. We investigated tissue microarrays of 31 invasive breast cancer patients, looking at quantity and topological distribution of CD3+, CD8+, CD20+, Ki67+, FoxP3+ TILs and CD3+/FoxP3+, CD8+/FoxP3+ cell ratios. We separately evaluated TILs at the invasive edge and at the center of the tumor, to find any clinical implications of tumor heterogeneity. No statistically significant difference was found in quantity and distribution of both TIL subsets and TIL ratios, by comparing patients who suffered from a local or distant recurrence of the tumor (relapse group: 13 patients) with patients not showing cancer relapse (non-relapse group: 18 patients). In the whole sample, we observed three main statistically significant positive correlations: (1) between CD3+ and CD8+ T-cells; (2) between FoxP3+ and Ki67+ lymphocyte infiltration; (3) between CD3+/FoxP3+ cell ratio (C3FR) and CD8+/FoxP3+ cell ratio (C8FR). Tumor heterogeneity and stronger positive TIL associations were found in the non-relapse group, where both CD3–CD8 and FoxP3-Ki67 inter-correlations were found to be significant at the center of the tumor, while the correlation between C3FR and C8FR was significant at the invasive edge. No correlations between TIL subsets were detected in the relapse group. Our findings suggest the existence of stronger inter-subtype lymphocytic networks in invasive breast cancer not showing recurrence. Further evaluations of clinical and topological correlations between and within TIL subsets are needed, in addition to the assessment of TIL quantification and distribution, in order to follow up on whether morphological evaluation of TILs might reveal the underlying lymphocytic functional connectivity and help relapse prediction.

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“…[1][2][3][4][5][6][7] This applies to the composition of the immune infiltrate at diagnosis, [1][2][3][4]8,9 as well as for the dynamic changes induced by anthracycline-based chemotherapy, in which an amelioration of the ratio of CD8…”

Section: Introductionmentioning

confidence: 99%

The ratio of CD8⁺/FOXP3 T lymphocytes infiltrating breast tissues predicts the relapse of ductal carcinoma in situ

Semeraro¹,

Adam

Stoll³

et al. 2016

OncoImmunology

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In a series of 248 tumor samples obtained from image-guided biopsies from patients diagnosed with ductal carcinoma in situ of the breast, we attempted to identify biomarkers that predict microinfiltration at definitive surgery or relapse during follow-up. For this, we used immunohistochemical methods, followed by automated image analyses, to measure the mean diameter of nuclei (which correlates with ploidy), the phosphorylation of eukaryotic initiation factor 2a (eIF2a, which reflects endoplasmic reticulum stress) as well as the density and ratio of CD8 C cytotoxic T lymphocytes and FOXP3 C regulatory T cells. The median nuclear diameter of malignant cells correlated with eIF2a phosphorylation (in cancerous tissue), which in turn correlated with the density of the CD8 C infiltrate and the CD8 C /FOXP3 ratio (both in cancerous and the adjacent non-cancerous parenchyma). Neither microinfiltration nor lymph node involvement was associated with the probability of relapse. Both correlated positively with the CD8 C /FOXP3 ratio in the malignant area. In contrast, relapse was associated with a paucity of the CD8 C infiltrate as well as an unfavorable CD8 C /FOXP3 ratio, both in malignant and non-malignant parenchyma. The combined analysis of the CD8 C /FOXP3 ratio in cancerous and non-cancerous tissues revealed a significant impact of their interaction on the probability of relapse, but not on the presence of microinfiltration or lymph node metastasis. Altogether, these results support the idea of an immunosurveillance system that determines the risk of relapse in ductal carcinoma in situ of the breast.

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Tumor-Infiltrating Lymphocytes: A Promising Biomarker in Breast Cancer

Cited by 31 publications

References 41 publications

Clinical Validity and Utility of Tumor-Infiltrating Lymphocytes in Routine Clinical Practice for Breast Cancer Patients: Current and Future Directions

Clinical Validity and Utility of Tumor-Infiltrating Lymphocytes in Routine Clinical Practice for Breast Cancer Patients: Current and Future Directions

Morphological Evaluation of Tumor-Infiltrating Lymphocytes (TILs) to Investigate Invasive Breast Cancer Immunogenicity, Reveal Lymphocytic Networks and Help Relapse Prediction: A Retrospective Study

The ratio of CD8⁺/FOXP3 T lymphocytes infiltrating breast tissues predicts the relapse of ductal carcinoma in situ

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Tumor-Infiltrating Lymphocytes: A Promising Biomarker in Breast Cancer

Cited by 31 publications

References 41 publications

Clinical Validity and Utility of Tumor-Infiltrating Lymphocytes in Routine Clinical Practice for Breast Cancer Patients: Current and Future Directions

Clinical Validity and Utility of Tumor-Infiltrating Lymphocytes in Routine Clinical Practice for Breast Cancer Patients: Current and Future Directions

Morphological Evaluation of Tumor-Infiltrating Lymphocytes (TILs) to Investigate Invasive Breast Cancer Immunogenicity, Reveal Lymphocytic Networks and Help Relapse Prediction: A Retrospective Study

The ratio of CD8+/FOXP3 T lymphocytes infiltrating breast tissues predicts the relapse of ductal carcinoma in situ

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The ratio of CD8⁺/FOXP3 T lymphocytes infiltrating breast tissues predicts the relapse of ductal carcinoma in situ